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TSUBAKI Masanobu

    Department of Pharmacy　Associate Professor
Last Updated :2023/12/05

Researcher Information

URL

J-Global ID

Research Interests

  • 転移抑制   抗癌剤耐性   分子標的薬   がん   

Research Areas

  • Life sciences / Pharmacology

Academic & Professional Experience

  • 2018 - Today  Kindai UniversityFaculty of Pharmacy准教授
  • 2013  Kindai UniversityFaculty of Pharmacy講師

Association Memberships

  • THE PHARMACEUTICAL SOCIETY OF JAPAN   THE JAPANESE ASSOCIATION FOR MOLECULAR TARGET THERAPY OF CANCER   THE JAPANESE CANCER ASSOCIATION   

Published Papers

  • Tomoya Takeda; Masanobu Tsubaki; Shuji Genno; Kenta Tokunaga; Remi Tanaka; Shozo Nishida
    International journal of molecular medicine 52 (3) 2023/09 [Refereed]
     
    Triple‑negative breast cancer (TNBC), a highly metastatic subtype of breast cancer, and it has the worst prognosis among all subtypes of breast cancer. However, no effective systematic therapy is currently available for TNBC metastasis. Therefore, novel therapies targeting the key molecular mechanisms involved in TNBC metastasis are required. The present study examined whether the expression levels of human epidermal growth factor receptor 3 (HER3) were associated with the metastatic phenotype of TNBC, and evaluated the potential of HER3 as a therapeutic target in vitro and in vivo. A new highly metastatic 4T1 TNBC cell line, termed 4T1‑L8, was established. The protein expression levels in 4T1‑L8 cells were measured using luminex magnetic bead assays and western blot analysis. The HER3 expression levels and distant metastasis‑free survival (DMFS) in TNBC were analyzed using Kaplan‑Meier Plotter. Transwell migration and invasion assays were performed to detect migration and invasion. The anti‑metastatic effects were determined in an experimental mouse model of metastasis. The results revealed that the increased expression of the HER3/Akt/mTOR pathway was associated with a greater level of cell migration, invasion and metastasis of TNBC cells. In addition, it was found that high expression levels of HER3 were associated with a poor DMFS. The inhibition of the HER3/Akt/mammalian target of rapamycin (mTOR) pathway decreased the migration, invasion and metastasis of TNBC cells by decreasing the expression of C‑X‑C chemokine receptor type 4 (CXCR4). Furthermore, treatment of metastatic TNBC cells with everolimus inhibited their migration, invasion and metastasis by decreasing CXCR4 expression. Thus, targeting the HER3/Akt/mTOR pathway opens up a new avenue for the development of therapeutics against TNBC metastasis; in addition, everolimus may prove to be an effective therapeutic agent for the suppression of TNBC metastasis.
  • Masayuki Shinkai; Motohiro Imano; Masashi Kohda; Tomoya Nakanishi; Yoko Hiraki; Takaomi Hagi; Hiroaki Kato; Osamu Shiraishi; Atsushi Yasuda; Masanobu Tsubaki; Shozo Nishida; Takushi Yasuda
    Langenbeck's archives of surgery 408 (1) 291 - 291 2023/07 [Refereed]
     
    PURPOSE: Gastric cancer patients with peritoneal metastasis (PM) are generally treated with systemic chemotherapy. When PM has disappeared because of chemotherapy, radical gastrectomy (so-called conversion surgery) is usually performed. We have previously reported the efficacy of conversion surgery, but there are no reports examining the efficacy of palliative gastrectomy for patients with residual PM after chemotherapy. The purpose of this study was to investigate the efficacy of palliative surgery for gastric cancer patients with PM who still have residual peritoneal dissemination after chemotherapy. METHODS: Twenty-five gastric cancer patients with PM confirmed by laparoscopy and who had received chemotherapy but who still had residual PM were included in this study. Among the 25 patients, palliative surgery was performed in 20 patients (PS group) and chemotherapy was continued in 5 patients (CTx group), and their therapeutic outcomes were compared. RESULTS: In the PS group, total and distal gastrectomies were performed. Clavien-Dindo grade I postoperative complications occurred in two patients (10%). There were no treatment-related deaths. Postoperative chemotherapy was performed all cases. In the PS group, the median survival time (MST) reached 22.5 months, with 1- and 2-year overall survival (OS) rates of 95% and 45%, respectively, whereas in the CTx group, the MST was 15.8 months, and the 1- and 2-year OS rates were 60% and 0%, respectively. The PS group had significantly longer OS than the CTx group (P=0.044). CONCLUSIONS: Palliative surgery is safe and may prolong survival in gastric cancer patients with residual PM after chemotherapy.
  • Masanobu Tsubaki; Tomoya Takeda; Takuya Matsuda; Kana Kishimoto; Honoka Takefuji; Yuzuki Taniwaki; Misa Ueda; Tadafumi Hoshida; Kazufumi Tanabe; Shozo Nishida
    Cancer cell international 23 (1) 73 - 73 2023/04 [Refereed]
     
    BACKGROUND: KRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice. METHODS: Cell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test. RESULTS: In this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo. CONCLUSION: Therefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.
  • Masanobu Tsubaki; Tomoya Takeda; Yuuichi Koumoto; Takehiro Usami; Takuya Matsuda; Shiori Seki; Kazuko Sakai; Kazuto Nishio; Shozo Nishida
    Cell proliferation 56 (6) e13420  2023/02 [Refereed]
     
    The development of BCR::ABL1 tyrosine kinase inhibitors (TKIs), such as dasatinib, has dramatically improved survival in cases of chronic myeloid leukaemia (CML). However, the development of resistance to BCR::ABL1 TKIs is a clinical problem. BCR::ABL1 TKI resistance is known to have BCR::ABL1-dependent or BCR::ABL1-independent mechanisms, but the mechanism of BCR::ABL1 independence is not well understood. In the present study, we investigated the mechanism of BCR::ABL1-independent dasatinib resistance. The expression and activation level of genes or proteins were evaluated using array CGH, real time PCR, or western blot analysis. Gene expression was modulated using siRNA-mediated knockdown. Cell survival was assessed by using trypan blue dye method. We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML.
  • Masanobu Tsubaki; Tomoya Takeda; Takuya Matsuda; Kana Kishimoto; Remi Tanaka; Katsumasa Tsurushima; Toshihiko Ishizaka; Shozo Nishida
    Clinical and experimental medicine 2022/11 [Refereed]
     
    Multiple myeloma (MM) frequently acquires multidrug resistance (MDR), which is due to poor prognosis. Our previous study indicated that high expression of Survivin and multidrug resistance protein 1 (MDR1) and decreased expression of Bim are associated with MDR in adriamycin- and dexamethasone-resistant cells. However, the fundamental mechanism of MDR in adriamycin- and dexamethasone-resistant MM cells is still unidentified. In this study, we examined the MDR mechanism in adriamycin- and dexamethasone-resistant cells. RPMI8226/ADM, ARH-77/ADM, RPMI8226/DEX, and ARH-77/DEX cells exhibited enhanced nuclear factor κB (NF-κB) p65, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Combination treatment with NF-κB p65, phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase 1/2 (MEK1/2) inhibitors resensitized to adriamycin and dexamethasone via increased Bim expression. Although treatment with MDR1 or Survivin siRNA did not overcome adriamycin and dexamethasone resistance in RPMI8226/ADM and RPMI8226/DEX cells, administration of Bim siRNA induced adriamycin and dexamethasone resistance in RPMI8226 cells. Moreover, low expression of Bim was related to poor prognosis in MM patients. These results indicate that activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance via decreasing Bim expression, and these signal inhibitor combinations overcome drug resistance in MM. These findings suggest that combination treatment with these inhibitors and adriamycin or dexamethasone may be a promising therapy for adriamycin- and dexamethasone-resistant MM.
  • Masanobu Tsubaki; Tomoya Takeda; Takuya Matsuda; Akihiro Kimura; Remi Tanaka; Sakiko Nagayoshi; Tadafumi Hoshida; Kazufumi Tanabe; Shozo Nishida
    BMB reports 56 (2) 78 - 83 2022/10 [Refereed]
     
    Chronic myeloid leukemia (CML) has a markedly improved prognosis with the use of breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitors (BCR-ABL1 TKIs). However, approximately 40% of patients are resistant or intolerant to BCR-ABL1 TKIs. Hypoxia inducible factor 1α (HIF-1α) is a hypoxia response factor that has been reported to be highly expressed in CML patients, making it a candidate target molecule for the therapy of CML as well as BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors induce cell death in CML cells and BCR-ABL1 TKI-resistant CML cells. We found that echinomycin and PX-478 induced cell death in BCR-ABL1 TKIs sensitive and resistant CML cells at similar concentrations while the cell sensitivity was not affected with imatinib or dasatinib in BCR-ABL1 TKIs resistant CML cells. In addition, echinomycin and PX-478 inhibited the c-Jun N-terminal kinase (JNK), Akt, and extracellular-regulated protein kinase 1/2 (ERK1/2) activation via suppression of BCR-ABL1 and Met expression in BCR-ABL1 sensitive and resistant CML cells. Moreover, treatment with HIF-1α siRNA induced cell death by inhibiting BCR-ABL1 and Met expression and activation of JNK, Akt, and ERK1/2 in BCR-ABL1 TKIs sensitive and resistant CML cells. These results indicated that HIF-1α regulates BCR-ABL and Met expression and is involved in cell survival in CML cells, suggesting that HIF-1α inhibitors induce cell death in BCR-ABL1 TKIs sensitive and resistant CML cells. These findings suggest that HIF-1α inhibitors may be beneficial as treatment for CML.
  • Katsumasa Tsurushima; Masanobu Tsubaki; Tomoya Takeda; Takuya Matsuda; Akihiro Kimura; Honoka Takefuji; Akane Okada; Chiaki Sakamoto; Toshihiko Ishizaka; Shozo Nishida
    International journal of molecular sciences 23 (15) 2022/08 [Refereed]
     
    Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic target. In the present study, we examined whether dimethyl fumarate (DMF), an NF-κB inhibitor, induces apoptosis in TNBC cells and enhances the apoptosis-inducing effect of paclitaxel and adriamycin. Cell survival was analyzed by the trypan blue assay and apoptosis assay. Protein detection was examined by immunoblotting. The activation of NF-κB p65 was correlated with poor prognosis in patients with TNBC. DMF induced apoptosis in MDA-MB-231 and BT-549 cells at concentrations that were non-cytotoxic to the normal mammary cell line MCF-10A. Furthermore, DMF inhibited NF-κB nuclear translocation and Survivin, XIAP, Bcl-xL, and Bcl-2 expression in MDA-MB-231 and BT-549 cells. Moreover, DMF enhanced the apoptosis-inducing effect of paclitaxel and adriamycin in MDA-MB-231 cells. These findings suggest that DMF may be an effective therapeutic agent for the treatment of TNBC, in which NF-κB is constitutively active. DMF may also be useful as an adjuvant therapy to conventional anticancer drugs.
  • Yusuke Morii; Hiromasa Senaha; Shunsuke Matsui; Kazuaki Okawa; Masanobu Tsubaki; Sumio Matzno; Kazunori Shimomura; Shozo Nishida
    Gan to kagaku ryoho. Cancer & chemotherapy 49 (7) 769 - 773 0385-0684 2022/07 [Refereed]
     
    Oxaliplatin is a platinum complex antineoplastic agent widely used for chemotherapy of colorectal cancer. However, one of its side effects is hypersensitivity reactions, the incidence of which increases with a cumulative dose, thereby posing a difficulty to continue oxaliplatin use. Our hospital changed the premedication of oxaliplatin in August 2009 and September 2012. We retrospectively investigated the usefulness of these premedication changes. The results showed no significant difference in the incidence of hypersensitivity between the control group(12.1%)and the group receiving H1 and H2-blockers (12.3%); however, the incidence of hypersensitivity was significantly reduced in the group receiving increased dexamethasone based on the number of courses(2.7%). Therefore, our regimen was found to be effective in preventing hypersensitivity reactions to oxaliplatin.
  • Tomoya Takeda; Masanobu Tsubaki; Takuya Matsuda; Akihiro Kimura; Minami Jinushi; Teruki Obana; Manabu Takegami; Shozo Nishida
    Oncology reports 47 (6) 2022/06 [Refereed]
     
    Tamoxifen resistance remains a major obstacle in the treatment of estrogen receptor (ER)‑positive breast cancer. In recent years, the crucial role of the epithelial‑mesenchymal transition (EMT) process in the development of drug resistance in breast cancer has been underlined. However, the central molecules inducing the EMT process during the development of tamoxifen resistance remain to be elucidated. In the present study, it was demonstrated that tamoxifen‑resistant breast cancer cells underwent EMT and exhibited an enhanced cell motility and invasive behavior. The inhibition of snail family transcriptional repressor 1 (Snail) and twist family BHLH transcription factor 1 (Twist) reversed the EMT phenotype and decreased the tamoxifen resistance, migration and invasion of tamoxifen‑resistant breast cancer cells. In addition, it was observed that the inhibition of epidermal growth factor receptor (EGFR) reversed the EMT phenotype in tamoxifen‑resistant MCF7 (MCF‑7/TR) cells via the downregulation of Snail and Twist. Notably, the EGFR inhibitor, gefitinib, decreased tamoxifen resistance, migration and invasion through the inhibition of Snail and Twist. On the whole, the results of the present study suggest that EGFR may be a promising therapeutic target for tamoxifen‑resistant breast cancer. Moreover, it was suggested that gefitinib may serve as a potent novel therapeutic strategy for breast cancer patients, who have developed tamoxifen resistance.
  • Katsumasa Tsurushima; Yukiko Yanagishita; Naoki Ogawa; Chika Fujii; Yukako Yasui; Tomoya Takeda; Masanobu Tsubaki; Shozo Nishida; Toshihiko Ishizaka; Jun Yamamura; Syunji Kamigaki
    Gan to kagaku ryoho. Cancer & chemotherapy 49 (6) 701 - 704 0385-0684 2022/06 [Refereed]
     
    Olanzapine(OLZ)is a multi-acting receptor-targeted antipsychotic drug approved in Japan in December 2017 for the treatment of anticancer drug-induced nausea and vomiting. However, the recommended doses and administration periods of OLZ in the literature and guidelines are varied. Reports on the efficacy and safety of OLZ combined with perioperative chemotherapy for breast cancer in Japanese patients are few. Moreover, the risk of nausea and vomiting during treatment with anticancer drugs in young and women patients remains to be high. In this study, we conducted an exploratory survey on the optimal duration of OLZ administration(days 1-4: 5 mg, before sleep)during perioperative breast cancer 5-fluorouracil, epirubicin, cyclophosphamide(FEC)therapy. We found that treatment with OLZ showed efficacy in improving nausea grade and maintaining relative dose intensity. Moreover, it could be used safely without interruption due to side effects, such as weight gain, elevation in blood glucose, somnolence, and insomnia. Prophylactic antiemetic therapy with OLZ administration (days 1-4: 5 mg)prior to sleep was effective in patients having FEC therapy-induced nausea and vomiting.
  • Tomoya Takeda; Yuuta Yamamoto; Masanobu Tsubaki; Takuya Matsuda; Akihiro Kimura; Natsumi Shimo; Shozo Nishida
    Oncology letters 23 (4) 106 - 106 2022/04 [Refereed]
     
    Colorectal cancer (CRC) is one of the most prevalent malignant diseases and metastasis is the leading cause of poor prognosis in patients with CRC. Further knowledge of the molecular mechanism underlying metastasis in CRC and the identification of new therapeutic targets are needed. Yes-associated protein (YAP) is a transcriptional regulator that is important in tumorigenesis and tumor cell proliferation. The present study investigated whether YAP was crucial for CRC migration and invasion. The protein expression levels were detected via western blotting, and migration and invasion were analyzed by Transwell migration and invasion assays. Subsequently, YAP expression was silenced using small interfering RNA. The mRNA expression levels were detected via reverse transcription-quantitative PCR and cell viability was assessed via Trypan blue exclusion assay. The results revealed that YAP protein levels were associated with migration and invasion of CRC cells. Notably, YAP small interfering RNA inhibited the migration and invasion of DLD-1 cells. In addition, the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway inhibitor LY294002 suppressed the migration and invasion of DLD-1 cells by decreasing the expression of YAP. Notably, the present study demonstrated that verteporfin mediated the suppression of migration and invasion of DLD-1 cells due to the decreased expression of YAP. Therefore, targeting YAP may be valuable for developing therapeutic strategies against CRC, and verteporfin may be an effective therapy to suppress the migration and invasion of CRC.
  • Morii, Y; Fujimoto, S; Nakahara, R; Okawa, K; Senaha, H; Fujiwara, K; Tsubaki, M; Matzno, S; Takegami, M; Shimomura, K; Nishida, S
    Die Pharmazie Avoxa - Mediengruppe Deutscher Apotheker GmbH 77 (2) 81 - 84 2022/02 [Refereed]
     
    Panitumumab, a therapeutic agent for unresectable advanced/recurrent colorectal cancer, is a human IgG2 monoclonal antibody that binds to and inhibits the activity of the epidermal growth factor receptor (EGFR). The onset of hypomagnesemia is a known side effect of anti-EGFR inhibitors, including panitumumab, and it is thought that inhibition of reabsorption of Mg in renal tubules is one of the causes. In addition, recent reports have shown that long-term administration of proton pump inhibitors (PPIs) reduces serum magnesium levels. Therefore, in this study, 102 patients who received oral PPIs treated with panitumumab were classified into a PPI combination group and a PPI non-combination group, and the effect of PPIs on the development of grade 2 or higher hypomagnesemia was investigated. The incidence of hypomagnesemia in the PPI combination group (46.9%, 15/32) was higher than that in the PPI non-combination group (25.7%, 18/70). A comparison of the backgrounds of the two groups of patients showed a significant difference in serum albumin levels. PPI administration was significantly associated with panitumumab-induced hypomagnesemia development when adjusted for known risk factors, serum albumin level, renal function, and oral magnesium oxide tablets in Cox proportional hazards regression analysis (hazard ratio 2.09; 95% confidence interval 1.03-4.22; P =0.040). These results indicate that detailed monitoring of serum magnesium levels is recommended for patients treated with panitumumab and co-administration of PPIs.
  • M Tsubaki; T Takeda; T Mastuda; A Kimura; M Yanae; A Maeda; T Hoshida; K Tanabe; S Nishida
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 73 (1) 2022/02 [Refereed]
     
    Statins and fibrates are frequently used to treat hyperlipidemia; however, these drugs may have adverse effects such as rhabdomyolysis. The incidence of rhabdomyolysis due to fibrates and statins is low (0.0028-0.0096%) when administered as monotherapy, however it increases to 0.015-0.021% when the drugs are used in combination. The mechanism underlying myotoxicity induced by the combination of statins and fibrates is yet unclear. Here, we investigated the mechanisms underlying induced myotoxicity in rat myoblasts L6 and differentiated L6 cells (myotubes) using a combination of statins and fibrates. We found that cell death induced by a combination of fluvastatin or simvastatin with bezafibrate or fenofibrate in L6 myoblasts and myotubes was mediated by inhibition of geranylgeranyl pyrophosphate (GGPP) production. Additionally, the drug combination inhibited Rho activation in L6 myoblasts and myotube cells. In L6 myoblasts, the combination of statins and bezafibrate enhanced p27 expression and induced G1 arrest and apoptosis. Furthermore, combined treatment suppressed Akt activation and enhanced Bim expression in L6 myotubes but did not affect extracellular regulated protein kinase 1/2 activation. These results suggested that combined administration of statins and fibrates induced death of L6 myoblasts and myotube cells by inhibiting GGPP biosynthesis and Rho pathway activation. Supplementation with GGPP may be therapeutically beneficial for preventing myotoxicity associated with combined statin and fibrates treatment.
  • Masayuki Shinkai; Motohiro Imano; Yoko Hiraki; Kota Momose; Hiroaki Kato; Osamu Shiraishi; Atsushi Yasuda; Masanobu Tsubaki; Shozo Nishida; Takushi Yasuda
    Langenbeck's archives of surgery 407 (3) 975 - 983 2022/01 [Refereed]
     
    PURPOSE: The prognosis of gastric cancer patients with peritoneal metastasis (PM) remains dismal with standard systemic chemotherapy. Intraperitoneal (i.p.) chemotherapy with paclitaxel (PTX) has local effects on intra-abdominal cancer cells. According to this phenomenon, we have developed regimens combining single i.p. PTX administration with systemic chemotherapy. This treatment strategy is very promising; however, the effect of "conversion surgery" in patients responding to this chemotherapy is unclear. Therefore, we performed a retrospective study to evaluate the safety and efficacy of conversion surgery for gastric cancer patients with PM. METHODS: We enrolled 52 gastric cancer patients with PM who were treated with single i.p. PTX plus systemic chemotherapy between 2005 and 2015. Conversion surgery was performed where PM was eliminated by combination chemotherapy. RESULTS: Among 52 gastric cancer patients, the disappearance of PM was confirmed in 33 patients (63.5%). Gastrectomy with D2 lymph node dissection was performed in all these patients. Histological response of grade ≥ 1b was achieved in 13 patients (39%). Clavien-Dindo grade II postoperative complications occurred in three patients (9%). There were no treatment-related deaths. The median survival time and 1-, 3-, and 5-year overall survival rates of the 33 patients who underwent conversion surgery were 30.7 months and 78.8%, 36.3%, and 24.2%, respectively, and those of the 19 patients who did not undergo surgery were 12.5 months and 52.6%, 5.2%, and 0%, respectively. CONCLUSION: Conversion surgery is safe and may prolong survival for gastric cancer patients with PM who have responded to single i.p. PTX plus systemic chemotherapy.
  • Tomoya Takeda; Masanobu Tsubaki; Natsuki Kato; Shuji Genno; Eri Ichimura; Aya Enomoto; Motohiro Imano; Takao Satou; Shozo Nishida
    Oncology letters 22 (6) 827 - 827 2021/12 [Refereed]
     
    Melanomas are highly malignant tumors that readily metastasize and have poor prognosis. Targeted therapy is a cornerstone of treatment for patients with melanoma. Although c-Kit gene aberration has found in 5-10% of melanoma cases, research on c-Kit inhibitors for melanoma with c-Kit aberration have been disappointing. Sorafenib is a tyrosine kinase inhibitor, whose targets include c-Kit, platelet derived growth factor receptor (PDGFR), VEGFR and RAF. The present study aimed to examine the effect of sorafenib on metastatic melanoma with c-Kit aberration. Cell viability was assessed via trypan blue assay. Migration and invasion were analyzed using cell culture inserts. The anti-metastatic effects and antitumour activity of sorafenib were determined in an in vivo model. Protein expression was detected via western blotting, and the expression of MMP and very late antigen (VLA) was detected via reverse transcription-quantitative PCR. It was identified that sorafenib decreased cell viability, migration and invasion in vitro. Furthermore, sorafenib inhibited metastasis and tumor growth in vivo. Mechanistically, sorafenib inhibited c-Kit, PDGFR, VEGFR, B-Raf and c-Raf phosphorylation both in vitro and in vivo. In addition, sorafenib reduced the expression levels of MMPs and VLA. Importantly, there was a significant effect of sorafenib treatment on overall survival in mice. Collectively, this study suggests that sorafenib may serve as a novel therapeutic option for melanoma with c-Kit dysregulation.
  • Daichiro Fujiwara; Masanobu Tsubaki; Tomoya Takeda; Makoto Miura; Shozo Nishida; Katsuhiko Sakaguchi
    European journal of hospital pharmacy : science and practice 28 (5) 266 - 270 2021/09 [Refereed]
     
    OBJECTIVES: The incidence of severe mucosal damage due to low nutritional status is high in patients receiving concurrent chemoradiotherapy (CCRT) for head and neck cancer. Objective assessments do not exist for discharge criteria after completion of CCRT. Although the prognostic nutritional index (PNI) is an objective indicator of postoperative outcomes in patients undergoing cancer surgery, the prognostic impact of the PNI in patients with head and neck cancer receiving CCRT is unexplored. We investigated whether the PNI could be an objective criterion for nutritional status and a discharge criterion after completion of CCRT. METHODS: We assessed the medical records of 23 patients with head and neck cancer who received triweekly cisplatin +radiotherapy (2 Gy ×35 fractions). We evaluated whether the PNI could be a useful evaluation indicator in patients with head and neck cancer receiving CCRT and determined the cut-off PNI value by receiver operating characteristic (ROC) curve analysis as a criterion for hospital discharge. RESULTS: The PNI pre-treatment and post-treatment values were 51.0 and 38.0, respectively (p<0.05). The median length of hospitalisation after therapy was 5 days in patients with grades 1 and 2 and 10 days in patients with grade 3 oral and pharyngeal mucositis (p<0.05). The optimal cut-off PNI value as a criterion for hospital discharge was found to be 40.4 (grades 1 and 2 mucositis) and 38.6 (grade 3 mucositis) by the ROC analysis. CONCLUSIONS: The PNI is a simple, objective and temporal indicator which is useful in assessing the nutritional status of patients with head and neck cancer. The PNI could be used as an objective indicator to determine the time of discharge after CCRT completion.
  • Masanobu Tsubaki; Tomoya Takeda; Takuya Matsuda; Yuuta Yamamoto; Aki Higashinaka; Kasane Yamamoto; Katsumasa Tsurushima; Toshihiko Ishizaka; Shozo Nishida
    Cytokine 144 155591 - 155591 2021/08 [Refereed]
     
    Interleukin 19 (IL-19) is a member of the IL-10 family of cytokines and is known as an inhibitory cytokine. IL-10, also an inhibitory cytokine, suppresses the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation. However, the effects of IL-19 on osteoclast differentiation are not currently well-understood. In this study, we examined whether IL-19 suppresses osteoclast differentiation in the mouse macrophage-like cell line RAW264.7. We found that IL-19 inhibited RANKL-induced osteoclast differentiation. In addition, IL-19 suppressed RANKL-induced NF-κB and p38 mitogen-activated protein kinase (p38MAPK) activation and c-Fos expression. Moreover, RANKL inhibited IL-19 mRNA expression and secretion in RAW264.7 cells, and the inhibition of the IL-19 function promoted osteoclast differentiation. These results indicate that IL-19 suppressed osteoclast differentiation via the inhibition of NF-κB and p38MAPK activation and c-Fos expression. Furthermore, IL-19 may maintain the osteoclast precursor state, such as monocytes and macrophages. These findings may be useful in the development of osteoclast inhibitors, thereby improving treatments for osteoclast activation-related diseases, such as osteoporosis.
  • Tomoya Takeda; Masanobu Tsubaki; Shuji Genno; Takuya Matsuda; Yuuta Yamamoto; Akihiro Kimura; Nao Shimizu; Shozo Nishida
    Clinical and experimental medicine 22 (2) 221 - 228 2021/07 [Refereed]
     
    Non-small cell lung cancer (NSCLC) is a highly aggressive cancer with one of the most prevalent malignant tumors. Metastasis in NSCLC is the major cause of treatment failure and cancer-related deaths. Yes-associated protein (YAP) is a transcriptional coactivator regulated by the evolutionarily conserved Hippo signaling pathway that regulates organ size, growth, and regeneration. YAP is highly expressed in several malignant tumor types. Furthermore, YAP promotes tumor initiation and/or progression in various types of cancer. However, it is unclear whether YAP contributes to the metastasis in NSCLC and serves as a useful therapeutic target. Here, we investigated whether levels of YAP correlate with metastatic phenotype in NSCLC cells and serve as a useful therapeutic target. We found that high levels of YAP associate with high cell migration, invasion, and metastasis in NSCLC cell lines. Furthermore, YAP siRNA decreased the migration and invasion in NSCLC cells. Additionally, verteporfin, an agent used for the treatment of symptomatic polypoidal choroidal vasculopathy, decreased the expression of YAP and inhibited migration, invasion, and metastasis in NSCLC cells. Thus, the study suggests that targeting YAP may present a new avenue to develop therapeutics against metastasis in NSCLC and that verteporfin has potential molecular therapeutic strategy for the treatment of metastatic NSCLC.
  • Yusuke Morii; Masanobu Tsubaki; Tomoya Takeda; Rie Otubo; Shiori Seki; Yuta Yamatomo; Motohiro Imano; Takao Satou; Kazunori Shimomura; Shozo Nishida
    European journal of pharmacology 898 173957 - 173957 2021/05 [Refereed]
     
    Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation in colon cancer contributes to the poor prognosis of the disease and chemoresistance of tumors. New therapies are needed; however, the lack of knowledge of the mechanism of chemoresistance has hindered progress. In this study, we investigated the mechanism of the reduced sensitivity of colon cancer cells to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), and the effects of perifosine, an Akt inhibitor that enhances the cytotoxicity of 5-FU and L-OHP in colon cancer cells harboring the PIK3CA mutation. The use of 5-FU or L-OHP alone or in combination induced significant death of Caco-2 cells (PIK3CA wild type), but only weakly decreased the viability of DLD-1 and SW948 cells harboring the PIK3CA mutation. The use of 5-FU and L-OHP, either alone or in combination, strongly suppressed Akt activation, Survivin, Bcl-2, and Bcl-xL expression, and enhanced Puma, phospho-p53, and p53 expression in Caco-2 cells than in DLD-1 cells. In addition, perifosine enhanced the cytotoxicity of the 5-FU and L-OHP combination, inhibited Akt activation and the expression of Survivin, Bcl-2, and Bcl-xL, and increased the expression of Puma, phospho-p53, and p53 in DLD-1 cells. These results indicate that PIK3CA mutation contributes to reduced sensitivity to 5-FU and L-OHP via Akt activation in colon cancer cells. Perifosine increases the efficacy of 5-FU and L-OHP by suppressing Akt activation. Thus, the use of an Akt inhibitor in combination with 5-FU and L-OHP may be beneficial in colon cancer with cells harboring the PIK3CA mutation.
  • Masanobu Tsubaki; Tomoya Takeda; Takuya Matsuda; Shiori Seki; Yoshika Tomonari; Shoutaro Koizumi; Miki Nagatakiya; Mai Katsuyama; Yuuta Yamamoto; Katsumasa Tsurushima; Toshihiko Ishizaka; Shozo Nishida
    Biomedicines 9 (1) 2021/01 [Refereed]
     
    Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway.
  • Masanobu Tsubaki; Shuuji Genno; Tomoya Takeda; Takuya Matsuda; Naoto Kimura; Yuuma Yamashita; Yuusuke Morii; Kazunori Shimomura; Shozo Nishida
    Biomedicines 9 (1) 2021/01 [Refereed]
     
    The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear whether rhosin, a Rho inhibitor, acts by suppressing metastasis by a downstream inhibition of Rho. In this study, we investigated this mechanism of metastasis in highly metastatic melanoma and breast cancer cells, and the mechanism of inhibition of metastasis by rhosin. We found that rhosin suppressed the RhoA and RhoC activation, the nuclear localization of YAP, but did not affect ERK1/2, Akt, or NF-κB activation in the highly metastatic cell lines B16BL6 and 4T1. High expression of YAP was associated with poor overall and recurrence-free survival in patients with breast cancer or melanoma. Treatment with rhosin inhibited lung metastasis in vivo. Moreover, rhosin inhibited tumor cell adhesion to the extracellular matrix via suppression of RHAMM expression, and inhibited SDF-1-induced cell migration and invasion by decreasing CXCR4 expression in B16BL6 and 4T1 cells. These results suggest that the inhibition of RhoA/C-YAP pathway by rhosin could be an extremely useful therapeutic approach in patients with melanoma and breast cancer.
  • Keisuke Tateishi; Masanobu Tsubaki; Tomoya Takeda; Yuuta Yamatomo; Motohiro Imano; Takao Satou; Shozo Nishida
    Journal of B.U.ON. : official journal of the Balkan Union of Oncology 26 (2) 606 - 612 2021 
    PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a major malignancy worldwide. Ras overexpression in HNSCC is known to promote tumor cell growth; therefore, inhibition of Ras activation could lead to tumor growth suppression in HNSCC patients. Here, we investigated the effect of FTI-277, a farnesyl transferase inhibitor, and GGTI-287, a geranyltransferase 1 inhibitor, on the Ras signaling pathway in HNSCC cell lines-HEp-2 and HSC-3. METHODS: Cell viability was analyzed using the trypan blue staining exclusion assay. The apoptosis of cells was assessed by flow cytometry and caspase activation analysis. The expression levels of proteins were examined using western blot analysis. RESULTS: FTI-277 and GGTI-287 induced cell death, enhanced caspase 3 activity, and increased the number of annexin V-positive cells in HEp-2 and HSC-3 cells. FTI-277 and GGTI-287 induced apoptosis in HSC-3 cells at much lower concentrations than that in HEp-2 cells. FTI-277 and GGTI-287 decreased the concentration of phosphorylated ERK1/2 and mTOR via membrane localization of Ras and enhanced Bim expression. Furthermore, FTI-277 and GGTI-287 induced cell death in v-H-Ras-transfected NIH3T3 (NW7) cells and not in empty vector-transfected NIH3T3 (NV20) cells. CONCLUSION: FTI-277 and GGTI-287 may be useful as potential therapeutic agents for treating HNSCC patients; moreover, farnesyl transferase and geranylgeranyltransferase 1 inhibitors can be further developed as anticancer agents.
  • Natsuki Kato; Keisuke Tateishi; Masanobu Tsubaki; Tomoya Takeda; Mikihiro Matsumoto; Katsumasa Tsurushima; Toshihiko Ishizaka; Shozo Nishida
    Pharmaceuticals (Basel, Switzerland) 14 (1) 2020/12 [Refereed]
     
    Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.
  • Tomoya Takeda; Masanobu Tsubaki; Shuji Genno; Chisato Nemoto; Yasuka Onishi; Yuuta Yamamoto; Motohiro Imano; Takao Satou; Shozo Nishida
    Oncology reports 44 (5) 2211 - 2218 2020/11 [Refereed]
     
    Imatinib is the gold standard in the conventional treatment of chronic myeloid leukemia (CML). However, some patients become resistant to imatinib therapy. To overcome this resistance, second‑generation (dasatinib, nilotinib, and bosutinib) and third‑generation (ponatinib) tyrosine kinase inhibitors (TKIs) have been developed and have been shown to be effective against refractory CML. Although these TKIs provide many benefits for patients with CML, advanced patients show resistance even to these TKIs. Therefore, novel therapeutic strategies are urgently needed for the treatment of TKI‑resistant CML patients. AT9283 is a multi‑targeted kinase inhibitor with potent activity against Janus kinase (JAK), Aurora kinases, and Abl. In the present study, we showed that AT9283 significantly decreased the cell viability of both TKI‑sensitive and TKI‑resistant CML cells as determined by trypan blue exclusion assay. In addition, cell cycle analysis, Annexin V assay, and caspase‑3/7 activity assay revealed that AT9283 increased the cell population in the G2/M phase and induced apoptosis. We investigated the molecular mechanisms underlying the decrease in cell viability upon treatment with AT9283 by western blotting. Interestingly, our results showed that AT9283 inhibited the expression of Aurora A, Aurora B, and downstream Histone H3 phosphorylation. In contrast, we observed no changes in the levels of Bcr‑Abl, signal transducer and activator of transcription 3 (STAT3), extracellular signal‑regulated kinase (ERK), and Akt phosphorylation. In addition, we found that AMG900, a selective Aurora A and Aurora B inhibitor, increased the G2/M phase cell population and induced apoptosis via inhibition of Aurora A and Aurora B in both TKI‑sensitive and TKI‑resistant CML cells. Our studies show that Aurora A and Aurora B are promising therapeutic targets for TKI‑sensitive and TKI‑resistant CML, and AT9283 may have potential clinical applications for the treatment of TKI‑resistant CML patients.
  • Masanobu Tsubaki; Shiori Seki; Tomoya Takeda; Akiko Chihara; Yuuko Arai; Yuusuke Morii; Motohiro Imano; Takao Satou; Kazunori Shimomura; Shozo Nishida
    International journal of molecular sciences 21 (21) 2020/10 [Refereed]
     
    Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated that HGF induces RANKL expression in osteoblasts and BMSCs, and investigated the mechanism of induction. We found that HGF and MM cell supernatants induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. In addition, HGF increased phosphorylation of Met and nuclear factor κB (NF-κB) in ST2 cells, MC3T3-E1 cells, or mouse BMSCs. Moreover, Met and NF-κB inhibitors suppressed HGF-induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. These results indicated that HGF promotes RANKL expression in osteoblasts and BMSCs via the Met/NF-κB signaling pathway, and Met and NF-κB inhibitors suppressed HGF-induced RANKL expression. Our findings suggest that Met and NF-κB inhibitors are potentially useful in mitigating MM-induced bone disease in patients expressing high levels of HGF.
  • Tomoya Takeda; Masanobu Tsubaki; Ryota Asano; Tatsuki Itoh; Motohiro Imano; Takao Satou; Shozo Nishida
    Journal of dermatological science 99 (3) 168 - 176 2020/09 [Refereed]
     
    BACKGROUND: Malignant melanoma is among the deadliest forms of skin cancers, and its incidence has been increasing over the past decades. In malignant melanoma, activation of the nuclear factor kappa B (NF-κB) promotes survival, migration, and invasion of cancer cells. Anti-NF-κB agents for treating metastatic melanoma would be beneficial, but no such drug is approved as either monotherapy or adjuvant therapy. Dimethyl fumarate (DMF) is an approved anti-inflammatory drug already in clinical use for psoriasis and multiple sclerosis. OBJECTIVE: We investigated the anti-tumour effect of DMF treatment in metastatic melanoma in vitro and in vivo. METHODS: The cell viability was assessed via trypan blue exclusion assay. The migration and invasion was analyzed in a Boyden chamber assay. The anti-metastatic effects and anti-tumour activity of DMF was determined in an in-vivo model. The expressions of NF-κB pathway and NF-κB regulatory proteins were detected via western blotting. RESULTS: DMF decreased the cell viability, migration and invasion in vitro. In addition, DMF inhibited spontaneous metastasis and tumour growth. Mechanistically, DMF prevented the nuclear translocation of NF-κB, whereas no changes were observed in the phosphorylation levels of inhibitor of kappa B (IκB). In addition, DMF inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs). Furthermore, DMF treatment decreased the expression of Survivin and Bcl-extra large (Bcl-XL) proteins. CONCLUSION: Our results suggest that DMF as a novel inhibitor of NF-κB may be a potential therapeutic agent for metastatic melanoma.
  • T Takeda; M Tsubak; S Genno; T Matsuda; Y Yamamoto; E Ueda; M Imano; T Satou; S Nishida
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 71 (4) 2020/08 [Refereed]
     
    Burkitt lymphoma (BL) is a highly aggressive form of non-Hodgkin's B-cell lymphoma. Currently, multi-agent chemotherapy regimens are being used to significantly improve cure rates and achieve complete remissions in BL patients. However, drug resistance can often occur within 6 months in BL patients, contributing to poor prognosis. Mounting evidence suggests that cell adhesion-mediated drug resistance (CAM-DR), caused by the interaction between the bone marrow microenvironment and tumour cells may play an important role in drug resistance to chemotherapy. However, the molecular mechanism underlying CAM-DR in BL has not been identified yet. In this study, we investigated the molecular mechanism responsible for CAM-DR in BL cells. We also examined the therapeutic targets of CAM-DR in BL cells and found CD49d and CD49e to be the important adhesion molecules involved. However, CD49a, CD49b, CD11a, CD29, CD18, and CD61 were not found to be associated with CAM-DR in BL cells. Furthermore, we clarified that CD49d- and CD49e-mediated CAM-DR could be attributed to an increase in the expression of B cell leukemia-xL (Bcl-xL) and survivin proteins, and a decrease in the expression of Bcl-2 associated X (Bax), Bcl-2 interacting mediator (Bim) and p53 upregulated modulator of apoptosis (PUMA) proteins via nuclear factor kappaB (NF-κB) activation. In addition, bortezomib was found to overcome CAM-DR in BL cells by inhibiting NF-κB. Thus, bortezomib may have potential clinical applications in the treatment of CD49d- and CD49e-mediated CAM-DR in BL patients.
  • Keiji Mashimo; Daichiro Fujiwara; Tadafumi Hoshida; Naomi Morimoto; Akihiro Noda; Tomoya Takeda; Masanobu Tsubaki; Shozo Nishida; Katsuhiko Sakaguchi
    Gan to kagaku ryoho. Cancer & chemotherapy (株)癌と化学療法社 47 (6) 993 - 995 0385-0684 2020/06 [Refereed]
     
    We had cases in which peripheral neuropathy was augmented after changing from mFOLFOX6, a chemotherapy for colorectal cancer, to FOLFIRI and comparatively examined disease status and trends. There were no shared points with respect to patient characteristics, timing of peripheral neuropathy augmentation, drug dosage, etc. It appeared that the change in chemotherapy itself had an effect on neuropathic symptoms. Regarding the change in chemotherapy, the therapeutic agent was switched from oxaliplatin to irinotecan; the cause was unknown, but some effects of these two drugs were suggested. Future investigation, including the examination of genetic mutations, is necessary.
  • Mitsuki Tabata; Masanobu Tsubaki; Tomoya Takeda; Keisuke Tateishi; Katsumasa Tsurushima; Motohiro Imano; Takao Satou; Toshihiko Ishizaka; Shozo Nishida
    BMC complementary medicine and therapies 20 (1) 84 - 84 2020/03 [Refereed]
     
    BACKGROUND: Current chemotherapies for Burkitt lymphoma (BL) have dramatically improved its clinical outcome. However, chemoresistance can lead to chemotherapy failure and very poor prognosis; thus, novel strategies are urgently required for patients with drug-resistant BL. To investigate the mechanisms underlying drug resistance in BL, we established drug-resistant BL cell lines: HS-Sultan/ADM (adriamycin-resistant), HS-Sultan/VCR (vincristine-resistant), HS-Sultan/DEX (dexamethasone-resistant), and HS-Sultan/L-PAM (melphalan-resistant). METHODS: Drug transporter and survival factor expression were investigated the using western blotting and real time polymerase chain reaction. Cell survival was analyzed by trypan blue dye exclusion method. RESULTS: The established cell lines acquired cross-resistance to adriamycin, vincristine, dexamethasone, and melphalan and exhibited 50% inhibitory concentration values 106-, 40-, 81-, and 45-fold higher than the parental cell lines, respectively. We found that protein and mRNA expression of MDR1 and Survivin were higher in drug-resistant BL cells than in the parent cells. Treatment with verapamil, an MDR1 inhibitor, or Survivin siRNA alongside each anti-cancer drug suppressed the proliferation of all drug-resistant BL cells. Src kinase activity was higher in all resistant cell lines than the parental cells; suppressing Src with dasatinib restored drug sensitivity by reducing MDR1 and Survivin expression. CONCLUSIONS: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.
  • Mitsuki Tabata; Masanobu Tsubaki; Tomoya Takeda; Keisuke Tateishi; Saho Maekawa; Katsumasa Tsurushima; Motohiro Imano; Takao Satou; Toshihiko Ishizaka; Shozo Nishida
    Clinical and experimental medicine 20 (1) 63 - 71 1591-8890 2020/02 [Refereed]
     
    Multiple myeloma (MM) is the second most common hematologic malignancy. In spite of the development of new therapeutic agents, MM remains incurable due to multidrug resistance (MDR) and the 5-year survival rate is approximately 50%. Thus, further study is needed to investigate the mechanism of MDR and improve MM prognosis. Heat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the stability of a number of client proteins, most of which are involved in tumor progression. Therefore, HSP90 inhibitors represent potential new therapeutic agents for cancer. Furthermore, inhibition of HSP90 leads to degradation of client proteins, overcoming acquired anti-cancer drug resistance. In this study, we assessed the role of HSP90 in MDR using established melphalan-resistant MM cells. We found that expression of HSP90 was higher in melphalan-resistant MM cells than in parent cells and that HSP90 inhibitors KW-2478 and NUV-AUY922 restored drug sensitivity to the level observed in parent cells. Activation of the unfolded protein response is a hallmark of MM, and expression of endoplasmic reticulum stress signaling molecules is reduced in melphalan-resistant cells; however, KW-2478 did not affect endoplasmic reticulum stress signaling. We demonstrated that treatment with KW-2478 decreased expression of Src, a client of HSP90, and suppressed the activity of ERK, Akt, and NF-κB. Our findings indicate that inhibition of HSP90 results in suppression of Src and its downstream effectors, including ERK, Akt, and NF-κB, and therefore that HSP90 inhibitors could be useful for treatment of MDR MM.
  • Masanobu Tsubaki; Tomoya Takeda; Masaki Noguchi; Minami Jinushi; Shiori Seki; Yuusuke Morii; Kazunori Shimomura; Motohiro Imano; Takao Satou; Shozo Nishida
    Cancers 11 (12) 2019/11 [Refereed]
     
    RAS and BRAF-mutated colorectal cancers are associated with resistance to chemotherapy and poor prognosis, highlighting the need for new therapeutic strategies. Although these cancers sometimes respond to mitogen activated protein kinase kinase (MEK) inhibitor treatment, they often acquire resistance via mechanisms, which are poorly understood. Here, we investigated the mechanism of MEK inhibitor resistance in primary- and acquired-resistant cells. Cell viability was examined using the trypan blue dye exclusion assay. Protein expression was analyzed by western blotting. Somatic mutations in colorectal cancer cells were investigated using the polymerase chain reaction array. PD0325901 and trametinib induced cell death in LoVo and Colo-205 cells but not in DLD-1 and HT-29 cells, which have a PIK3CA mutation constitutively activating Akt and NF-κB. Treatment with PD0325901 and trametinib suppressed ERK1/2 activation in all four cell lines but only induced Akt and NF-κB activation in DLD-1 and HT-29 cells. Inhibition of Akt but not NF-κB, overcame MEK inhibitor resistance in DLD-1 and HT-29 cells. Acquired-resistant LoVo/PR, Colo-205/PR and LoVo/TR cells have constitutively active Akt due to a M1043V mutation in the kinase activation loop of PIK3CA and Akt inhibitor resensitized these cells to MEK inhibitor. These results demonstrate that the overactivation of Akt plays a critical role in MEK inhibitor primary and acquired resistance and implicate combined Akt/MEK inhibition as a potentially useful treatment for RAS/BRAF-mutated colorectal cancer.
  • Masanobu Tsubaki; Tomoya Takeda; Naoya Obata; Keishi Kawashima; Mitsuki Tabata; Motohiro Imano; Takao Satou; Shozo Nishida
    Journal of cellular physiology 234 (10) 17975 - 17989 0021-9541 2019/08 [Refereed]
     
    Malignant melanoma is a highly aggressive skin cancer, and the overall median survival in patients with metastatic melanoma is only 6-9 months. Although molecular targeted therapies have recently been developed and have improved the overall survival, melanoma patients may show no response and acquisition of resistance to these drugs. Thus, other molecular approaches are essential for the treatment of metastatic melanoma. In the present study, we investigated the effect of cotreatment with dacarbazine and statins on tumor growth, metastasis, and survival rate in mice with metastatic melanomas. We found that cotreatment with dacarbazine and statins significantly inhibited tumor growth and metastasis via suppression of the RhoA/RhoC/LIM domain kinase/serum response factor/c-Fos pathway and enhanced p53, p21, p27, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase 1 expression in vivo. Moreover, the cotreatment significantly improved the survival rate in metastasis-bearing mice. Importantly, treatment with dacarbazine plus 100 mg/kg simvastatin or fluvastatin prevented metastasis-associated death in 4/20 mice that received dacarbazine + simvastatin and in 8/20 mice that received dacarbazine + fluvastatin (survival rates, 20% and 40%, respectively). These results suggested that cotreatment with dacarbazine and statins may thus serve as a new therapeutic approach to control tumor growth and metastasis in melanoma patients.
  • Keiji Mashimo; Masanobu Tsubaki; Tomoya Takeda; Ryota Asano; Minami Jinushi; Motohiro Imano; Takao Satou; Katsuhiko Sakaguchi; Shozo Nishida
    Clinical and experimental medicine 19 (1) 133 - 141 1591-8890 2019/02 [Refereed]
     
    The survival and growth of multiple myeloma (MM) cells are facilitated by cell-cell interactions with bone marrow stromal cells and the bone marrow microenvironment. These interactions induce de novo drug resistance known as cell adhesion-mediated drug resistance. Our previous results recently revealed that the receptor activator of NF-κB (RANK) ligand (RANKL), which is expressed by bone marrow stromal cells, contributes to anti-cancer drug resistance through the activation of various signaling molecules and suppression of Bim expression in RANK-expressing MM cells. However, the detailed mechanisms underlying RANKL-induced drug resistance remain uncharacterized. In the present study, we investigated the mechanism of RANKL-induced drug resistance in RANK-expressing MM cell lines. We found treatment of MM cells with RANKL-induced c-Src phosphorylation and activation of the downstream signaling molecules Akt, mTOR, STAT3, JNK, and NF-κB. In addition, treatment with dasatinib, a c-Src inhibitor, overcame RANKL- and bone marrow stromal cell-induced drug resistance to adriamycin, vincristine, dexamethasone, and melphalan by suppressing c-Src, Akt, mTOR, STAT3, JNK, and NF-κB activation and enhancing expression of Bim. Overall, RANKL- and bone marrow stromal cell-induced drug resistance correlated with the activation of c-Src signaling pathways, which caused a decrease in Bim expression. Dasatinib treatment of RANK-expressing MM cells re-sensitized them to anti-cancer drugs. Therefore, inhibition of c-Src may be a new therapeutic approach for overcoming RANKL-induced drug resistance in patients with MM.
  • Masayuki Shinkai; Motohiro Imano; Yasutaka Chiba; Mitsuru Iwama; Osamu Shiraisi; Atsushi Yasuda; Masanobu Tsubaki; Shozo Nishida; Yutaka Kimura; Takushi Yasuda
    Journal of surgical oncology 119 (1) 56 - 63 0022-4790 2019/01 [Refereed]
     
    BACKGROUND: We carried out a phase II trial to evaluate the feasibility and efficacy of neoadjuvant chemotherapy comprising a single intraperitoneal administration of paclitaxel, followed by intravenous administrations of paclitaxel and cisplatin with S-1 for clinical stage III gastric cancer. METHODS: Patients with potentially resectable gastric cancer were eligible. A laparoscopic survey was performed to confirm CY0 and P0. Intraperitoneal paclitaxel (60 mg/m 2 ) was administered, followed by systemic chemotherapy. Surgery was performed after two cycles of chemotherapy. The primary endpoint was the response rate of chemotherapy. Secondary endpoints were adverse events, pathological response rate, and overall survival rate. RESULTS: Twenty patients were enrolled. Planned cycles were completed in all patients. Grade 3/4 leukopenia and grade 3/4 neutropenia were observed in four (20%) and seven (35%) patients, respectively. The overall response rate was 70% (partial response: 14, stable disease: 5, progressive disease: 1). All patients underwent R0 gastrectomy with D2 lymph-node dissection, with no surgery-related deaths. The pathological response rate was 65% (13 of 20). The 3- and 5-year overall survival rates were 90.0% and 77.1%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy including intraperitoneal paclitaxel followed by sequential intravenous paclitaxel and cisplatin with S-1 for resectable advanced gastric cancer is feasible and effective.
  • Masanobu Tsubaki; Tomoya Takeda; Yoshika Tomonari; Yu-Ichi Koumoto; Motohiro Imano; Takao Satou; Shozo Nishida
    Laboratory investigation; a journal of technical methods and pathology 99 (1) 72 - 84 0023-6837 2019/01 [Refereed]
     
    Multiple myeloma (MM) commonly displays multidrug resistance and is associated with poor prognosis. Therefore, it is important to identify the mechanisms by which MM cells develop multidrug resistance. Our previous study showed that multidrug resistance is correlated with overexpression of multidrug resistance protein 1 (MDR1) and Survivin, and downregulation of Bim expression in melphalan-resistant RPMI8226/L-PAM cells; however, the underlying mechanism of multidrug resistance remains unclear. In the present study, we investigated the mechanism of multidrug resistance in melphalan-resistant cells. We found that RPMI8226/L-PAM and ARH-77/L-PAM cells showed increased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt, and nuclear localization of nuclear factor κB (NF-κB). The combination of ERK1/2, Akt, and NF-κB inhibitors with melphalan reversed melphalan resistance via suppression of Survivin expression and enhanced Bim expression in melphalan-resistant cells. In addition, RPMI8226/L-PAM and ARH-77/L-PAM cells overexpressed hypoxia-inducible factor 1α (HIF-1α) via activation of ERK1/2, Akt, and NF-κB. Moreover, suppression of HIF-1α by echinomycin or HIF-1α siRNA resensitized RPMI8226/L-PAM cells to melphalan through downregulation of Survivin expression and upregulation of Bim expression. These results indicate that enhanced Survivin expression and decreased Bim expression by HIF-1α via activation of ERK1/2, Akt, and NF-κB play a critical role in melphalan resistance. Our findings suggest that HIF-1α, ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of melphalan-resistant MM.
  • 婦人科悪性腫瘍におけるパクリタキセル・カルボプラチン療法での後発品製剤安全性の検討(An Analysis of Generic Drug Safety in Paclitaxel and Carboplatin Chemotherapy for Gynecologic Malignancies)
    藤本 伸一郎; 柳江 正嗣; 淺野 肇; 武田 朋也; 椿 正寛; 藤原 季美子; 月岡 康行; 松野 純男; 森嶋 祥之; 西田 升三
    ジェネリック研究 日本ジェネリック医薬品・バイオシミラー学会 12 (2) 74 - 79 1881-9117 2018/12 [Refereed]
     
    わが国では後発医薬品への切り替えが推進されているが、切り替え時の問題点として、臨床試験における同等性の報告が義務付けられていないことが挙げられる。安全域が狭いがん化学療法の分野において、切り替えによる有害事象発現の差異が治療に影響する可能性は高く、実臨床での薬剤評価が必要と考える。しかし、後発医薬品への切り替えに際し、製剤毎での比較報告はあるものの、後発医薬品を併用したレジメンとしての報告は少なく、十分なエビデンスが少ないなかで治療が行われているのが現状である。本検討では婦人科悪性腫瘍における重要なレジメンである、パクリタキセル・カルボプラチン療法における切り替えによる安全性の差異を確認した。結果として、血液毒性、筋肉痛及び関節痛については、切り替え後も同等である可能性が示唆された。他の非血液毒性については、切り替えによりオッズ比は低下傾向であったが、同等性は保証されなかった。また、治療中に減量を必要とした症例数に有意な差は認められず、切り替え後も安全性が保たれていることが示唆された。今後も症例数を重ね、より科学的根拠のある報告をする必要がある。(著者抄録)
  • Masayuki Shinkai; Motohiro Imano; Yasutaka Chiba; Yoko Hiraki; Hiroaki Kato; Mitsuru Iwama; Osamu Shiraisi; Atsushi Yasuda; Masahiro Tsubaki; Shozo Nishida; Yutaka Kimura; Takushi Yasuda
    Anticancer research 38 (10) 5969 - 5974 0250-7005 2018/10 [Refereed]
     
    BACKGROUND/AIM: A preliminary study evaluating the feasibility of single intraperitoneal (IP) administration of paclitaxel followed by paclitaxel and cisplatin with S-1 (PCS) systemic chemotherapy for cytology-positive (CY1) gastric cancer. PATIENTS AND METHODS: Staging laparoscopy was performed to confirm CY1 and P0 status. Initially, patients received IP paclitaxel. Beginning 7 days later PCS was given every 3 weeks followed by second-look laparoscopy. RESULTS: Nine patients were enrolled. The toxic effects of IP and systemic chemotherapy were acceptable. After chemotherapy, 8 patients converted from CY1P0 to CY0P0 and 1 patient from CY1P0 to CY1P1. Gastrectomy was performed on 8 patients except for the CY1P1 patient. Four patients were alive without recurrence. The 2-year overall and progression-free survival rates were 76% and 65%, respectively. CONCLUSION: Combination chemotherapy with IP paclitaxel and sequential PCS is safe and may be effective for CY1 gastric cancer.
  • Masayuki Shinkai; Motohiro Imano; Yasutaka Chiba; Yoko Hiraki; Hiroaki Kato; Mitsuru Iwama; Osamu Shiraishi; Atsushi Yasuda; Masahiro Tsubaki; Shozo Nishida; Yutaka Kimura; Takushi Yasuda
    Anticancer research 38 (10) 5975 - 5981 0250-7005 2018/10 [Refereed]
     
    AIM: To conduct a phase II study of single intraperitoneal (i.p.) administration of paclitaxel followed by paclitaxel, cisplatin, and S-1 (PCS) chemotherapy for patients with gastric cancer with peritoneal metastasis (PM). PATIENTS AND METHODS: Staging laparotomy was performed to confirm PM. Initially, patients received i.p. paclitaxel. Beginning 7 days later, PCS was given every 3 weeks followed by second-look laparoscopy. Primary and secondary endpoints were the overall survival (OS) rate, and response rate and patient safety, respectively. RESULTS: Seventeen patients were enrolled. The overall response rate was 70.5% (12/17). Grade 3/4 toxic effects included neutropenia and leukopenia. After chemotherapy, PM disappearance was confirmed in 11 patients. Gastrectomy was eventually performed in 11 patients. The 1-year OS rate was 82.4% and the median survival time was 23.9 months considering the overall cohort. CONCLUSION: Combination chemotherapy with i.p. paclitaxel and PCS is well tolerated and effective in patients with gastric cancer with PM.
  • Masanobu Tsubaki; Tomoya Takeda; Mikihiro Matsumoto; Natsuki Kato; Shota Yasuhara; Yu-Ichi Koumoto; Motohiro Imano; Takao Satou; Shozo Nishida
    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 (10) 1010428318808670 - 1010428318808670 1010-4283 2018/10 [Refereed]
     
    Chemotherapy-induced neuropathy is a highly problematic, dose-limiting effect of potentially curative regimens of cancer chemotherapy. When neuropathic pain is severe, patients often either switch to less-effective chemotherapy agents or choose to discontinue chemotherapy entirely. Conventional chemotherapy drugs used to treat lung and breast cancer, multiple myeloma, and lymphoma include paclitaxel, vincristine, and bortezomib. Approximately 68% of patients receiving these anticancer drugs develop neuropathy within the first month of treatment, and while strategies to prevent chemotherapy-induced neuropathy have been investigated, none have yet been proven as effective. Recent reports suggest that chemotherapy-induced neuropathy is associated with signal transduction molecules, including protein kinase C and mitogen-activated protein kinases. It is currently unclear whether protein kinase C inhibition can prevent chemotherapy-induced neuropathy. In this study, we found that tamoxifen, a protein kinase C inhibitor, suppressed paclitaxel-, vincristine-, and bortezomib-induced cold and mechanical allodynia in mice. In addition, chemotherapy drugs induce neuropathy via the protein kinase C/extracellular signal-regulated kinase pathway in the spinal cord in lumbar segments 4-6 and dorsal root ganglions. In addition, tamoxifen was shown to act synergistically with paclitaxel to inhibit tumor-growth in mice injected with tumor cells. Our results indicated that paclitaxel-, vincristine-, and bortezomib-induced neuropathies were associated with the protein kinase C/extracellular signal-regulated kinase pathway in the lumbar spinal cord and dorsal root ganglions, which suggest that protein kinase C inhibitors may be therapeutically effective for the prevention of chemotherapy-induced neuropathy when administered with standard chemotherapy agents.
  • Masanobu Tsubaki; Tomoya Takeda; Yoshika Tomonari; Kenji Mashimo; Yu-Ichi Koumoto; Sachi Hoshida; Tatsuki Itoh; Motohiro Imano; Takao Satou; Katsuhiko Sakaguchi; Shozo Nishida
    Journal of cellular physiology 233 (5) 4258 - 4271 0021-9541 2018/05 [Refereed]
     
    Several autocrine soluble factors, including macrophage inflammatory protein-1α (MIP-1α), tumor necrosis factor-α, and hepatocyte growth factor, promote cell survival and growth in multiple myeloma (MM) cells. We hypothesized that inhibition of the MIP-1α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, an MIP-1α neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of melphalan or bortezomib on MM cells. In addition, melphalan resistance cells (RPMI8226/L-PAM and HS-sultan/L-PAM cells) secreted MIP-1α and neutralizing antibody of MIP-1α partially overcame melphalan resistance. Moreover, combination treatment with MIP-1α neutralizing antibody and melphalan or bortezomib inhibited extracellular signal regulated kinase 1/2 (ERK1/2), Akt, and mammalian target of rapamycin (mTOR) activation, Bcl-2, Bcl-xL, and Survivin expression, and upregulated the expression of Bim and cleaved Poly (ADP-ribose) polymerase (PARP). Treatment of IM9 cells with MIP-1α siRNA suppressed the activation of ERK1/2, Akt, and mTOR, and enhanced the cytotoxic effect of melphalan and bortezomib. These results indicate that MIP-1α neutralizing antibodies or MIP-1α siRNA enhance the cytotoxic effect of melphalan and bortezomib by suppressing the chemokine receptor/ERK and chemokine receptor/Akt/mTOR pathways. The inhibition of MIP-1α may thus provide a new therapeutic approach to control tumor progression and bone destruction in patients with MM.
  • Masanobu Tsubaki; Tomoya Takeda; Yoshika Tomonari; Keishi Kawashima; Tatsuki Itoh; Motohiro Imano; Takao Satou; Shozo Nishida
    Journal of cellular physiology 233 (4) 3638 - 3647 0021-9541 2018/04 [Refereed]
     
    Pioglitazone is an anti-diabetic agent that belongs to the thiazolidinedione class, which target peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor in the nuclear receptor family. Different cancer cells expressing high levels of PPARγ and PPARγ ligands induce cell cycle arrest, cell differentiation, and apoptosis. However, the mechanisms underlying these processes remain unknown. Here, we investigated the mechanism underlying pioglitazone-induced apoptosis in human cancer cells. We showed that at similar concentrations, pioglitazone induced death in cancer cells expressing high or low levels of PPARγ. Combined treatment of pioglitazone and GW9662, a PPARγ antagonist, did not rescue this cell death phenotype. Z-VAD-fmk, a pan-caspase inhibitor, did not reverse pioglitazone-induced apoptosis in cancer cells expressing PPARγ at high or low levels. Pioglitazone suppressed the activation of signal transducers and activator of transcription 3 (STAT3) and Survivin expression, and enhanced the apoptosis-inducing factor (AIF) levels in these cells. Furthermore, pioglitazone enhanced the cytotoxic effect of cisplatin and oxaliplatin by suppressing Survivin and increasing AIF expression. These results indicated that pioglitazone induced apoptosis via a PPARγ-independent pathway, thus describing pioglitazone as a potential therapeutic agent for controlling the progression of different cancers.
  • Tomoya Takeda; Masanobu Tsubaki; Yoshika Tomonari; Keishi Kawashima; Tatsuki Itoh; Motohiro Imano; Takao Satou; Shozo Nishida
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 100 486 - 494 0753-3322 2018/04 [Refereed]
     
    Bavachin is a phytoestrogen purified from natural herbal plants such as Psoralea corylifolia. In this study, we examined the effect of bavachin in multiple myeloma (MM) cell lines. We found that bavachin decreased the viability of MM cell lines, but was not cytotoxic towards normal cells. It inhibited the activation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Furthermore, bavachin increased the expression of p53 and NOXA, and decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, B cell lymphoma-extra large (Bcl-xL), and Bcl-2. Additionally, bavachin induced apoptosis by the activation of caspase-3 and caspase-9, implicating the involvement of the mitochondrial pathway. Our results suggest that bavachin induces apoptosis through the inhibition of NF-κB and STAT3 activation in MM cell lines. Most importantly, few NF-κB and STAT3 inhibitors with high efficiency, specificity, and safety are currently available for clinical cancer therapy. Hence, bavachin, which targets NF-κB and STAT3, is a potential anticancer agent for the treatment of MM.
  • Masanobu Tsubaki; Tomoya Takeda; Ryo-Ta Asano; Tomoyuki Matsuda; Shin-Ichiro Fujimoto; Tatsuki Itoh; Motohiro Imano; Takao Satou; Shozo Nishida
    Toxicology in vitro : an international journal published in association with BIBRA 46 284 - 293 0887-2333 2018/02 [Refereed]
     
    Oral mucositis is a common adverse effect of chemotherapy that limits the required dose of chemotherapeutic agents. Numerous attempts to mitigate chemotherapy-induced oral mucositis have failed to identify an appropriate treatment. Recently, it has been indicated that rebamipide prevents chemoradiotherapy-induced oral mucositis in patients. However, the details of the underlying mechanism involved in the cytoprotective effect of rebamipide remain obscure. In the present study, we investigated the mechanism behind rebamipide cytoprotective effect in the oral mucosa using primary normal human oral keratinocytes (NHOK cells). We found that rebamipide prevented 5-fluorouracil (5-FU)-induced cell death in NHOK cells. In addition, rebamipide increased the levels of phosphorylated Akt and mTOR, enhanced the Bcl-2 and Bcl-xL expressions, and suppressed the expression of Bax and Bim. This is in contrast to 5-FU-induced suppression of Akt and mTOR activation, Bcl-2 and Bcl-xL expressions, and the enhanced expression of Bax and Bim. These findings suggest that rebamipide can potentially be used for the protection of oral mucosa from chemotherapy-induced mucositis. This is the first study that elucidates the specific molecular pathway for the cytoprotective effect of rebamipide.
  • Masanobu Tsubaki; Tomoya Takeda; Mikihiro Matsumoto; Natsuki Kato; Ryo-Ta Asano; Motohiro Imano; Takao Satou; Shozo Nishida
    American journal of cancer research 8 (7) 1239 - 1248 2156-6976 2018 [Refereed]
     
    Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of some anti-cancer drugs and leads to discontinuation of chemotherapy and detrimental dose reductions, thereby affecting the quality of life of cancer patients. Currently, no treatment can effectively prevent or treat chemotherapy-induced neuropathy. Therefore, understanding its underlying molecular mechanisms may help to identify novel therapies for treating it. Some disease-induced neuropathy involve the activation of mitogen-activated protein kinases (MAPKs), such as extracellular-regulated protein kinase 1/2 (ERK1/2). In the present study, we investigated whether ERK1/2 inhibition can prevent chemotherapy-induced neuropathy. We found that trametinib, an MEK inhibitor, suppressed oxaliplatin-, paclitaxel-, vincristine-, and bortezomib-induced cold and mechanical allodynia in mice. In addition, treatment with oxaliplatin, paclitaxel, vincristine, or bortezomib enhanced ERK1/2 and c-Jun N-terminal kinase (JNK) phosphorylation in the spinal cord lumbar segments 4-6, and when combined with trametinib, can prevent chemotherapy-induced neuropathy via the suppression of ERK1/2 activation, but does not affect JNK activation. In conclusion, we demonstrated that the disruption of this pathway by MEK inhibitors suppresses oxaliplatin-, paclitaxel-, vincristine-, and bortezomib-induced neuropathy. This suggests that inhibition of the MEK/ERK pathway could prevent chemotherapy-induced neuropathy and MEK inhibitors could be used in combination with anti-tumor drugs during pharmacotherapy.
  • Masanobu Tsubaki
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan (公社)日本薬学会 138 (12) 1461 - 1466 0031-6903 2018 [Refereed]
     
    Resistance to the breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor (TKI), imatinib, poses a major problem in the treatment of chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, the basis of this BCR-ABL1-independent resistance in the absence of such mutation remains to be elucidated. The aim of the present study is to identify the mechanism of imatinib resistance in CML. To gain insight into BCR-ABL1-independent imatinib resistance mechanisms, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, focusing on the receptor tyrosine kinase MET. Treatment with an MET inhibitor resensitized K562/IR cells to BCR-ABL TKIs. A treatment combining imatinib and a MET inhibitor in K562/IR cells inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Moreover, the combination of MET inhibitor and imatinib suppressed tumor growth in vivo. These results indicate that the activation of MET/ERK and MET/JNK are potential mechanisms of BCR-ABL TKI resistance. Our findings provide new and important information concerning the mechanisms of imatinib resistance in CML, and reveal new proteins potentially involved in BCR-ABL TKI resistance.
  • Daichiro Fujiwara; Masanobu Tsubaki; Tomoya Takeda; Yoshika Tomonari; Yu-Ichi Koumoto; Katsuhiko Sakaguchi; Shozo Nishida
    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine SAGE Publications Ltd 39 (10) 1010428317734947 - 1010428317734947 1423-0380 2017/10 [Refereed]
     
    Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.
  • Masashi Yanae; Shinichiro Fujimoto; Kaori Tane; Maki Tanioka; Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Yoshiyuki Morishima; Yasutaka Chiba; Shintaro Takao; Yoshifumi Komoike; Junji Tsurutani; Kazuhiko Nakagawa; Shozo Nishida
    Journal of Bone Oncology Elsevier GmbH 8 18 - 22 2212-1374 2017/09 [Refereed]
     
    Background Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. Methods We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. Results The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30–87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647–9.481 p = 0.002). Conclusions Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.
  • Masashi Yanae; Shinichiro Fujimoto; Kaori Tane; Maki Tanioka; Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Yoshiyuki Morishima; Yasutaka Chiba; Shintaro Takao; Yoshifumi Komoike; Junji Tsurutani; Kazuhiko Nakagawa; Shozo Nishida
    Journal of bone oncology ELSEVIER SCIENCE BV 8 18 - 22 2212-1366 2017/09 [Refereed]
     
    BACKGROUND: Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. METHODS: We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. RESULTS: The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). CONCLUSIONS: Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.
  • Masanobu Tsubaki; Tomoya Takeda; Toshiki Kino; Kazuko Sakai; Tatsuki Itoh; Motohiro Imano; Takashi Nakayama; Kazuto Nishio; Takao Satou; Shozo Nishida
    Oncotarget 8 (24) 38717 - 38730 2017/06 [Refereed]
     
    Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, and focused on MET. Treatment with a MET inhibitor resensitized K562/IR cells to BCR-ABL1 TKIs. Combined treatment of K562/IR cells with imatinib and a MET inhibitor suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Our findings implicate the MET/ERK and MET/JNK pathways in conferring resistance to imatinib, providing new insights into the mechanisms of BCR-ABL1 TKI resistance in CML.
  • Masanobu Tsubaki; Daichiro Fujiwara; Tomoya Takeda; Toshiki Kino; Yoshika Tomonari; Tatsuki Itoh; Motohiro Imano; Takao Satou; Katsuhiko Sakaguchi; Shozo Nishida
    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY WILEY 44 (2) 222 - 234 1440-1681 2017/02 [Refereed]
     
    Statins induce apoptosis of tumour cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanisms remain poorly understood. The present study showed that the induction of apoptosis by statins in four different human head and neck squamous cell carcinoma ( HNSCC) cell lines, HSC-3, HEp-2, Ca9-22, and SAS cells was mediated by increased caspase-3 activity. Statins induced apoptosis by the suppression of geranylgeranyl pyrophosphate biosynthesis. Furthermore, statins decreased the levels of phosphorylated ERK and mTOR by inhibiting the membrane localization of Ras and enhancing Bim expression in HSC-3 and HEp-2 cells. We also found that in all the cell types analyzed, the IC50 values for fluvastatin and simvastatin were highest in HEp-2 cells. In addition, HSC-3, Ca9-22, and SAS cells had higher Ras expression and membrane localization, higher activation of ERK1/2 and mTOR, and lower levels of Bim expression than HEp-2 cells. Our results indicate that statins induce apoptosis by increasing the activation of caspase-3 and by enhancing Bim expression through inhibition of the Ras/ERK and Ras/mTOR pathways. Furthermore, the sensitivity of HNSCC cells to statin treatment was closely related to Ras expression and prenylation levels, indicating that statins may act more effectively against tumours with high Ras expression and Ras-variability. Therefore, our findings support the use of statins as potential anticancer agents.
  • Daichiro Fujiwara; Keiji Mashimo; Kayo Kimura; Akihiro Noda; Kazuo Taki; Hiroshi Yoshibayashi; Tomoya Takeda; Masanobu Tsubaki; Shozo Nishida; Katsuhiko Sakaguchi
    Gan to kagaku ryoho. Cancer & chemotherapy Japanese Journal of Cancer and Chemotherapy Publishers Inc. 44 (2) 149 - 152 0385-0684 2017/02 [Refereed]
     
    Febrile neutropenia(FN)is one of the serious treatment-related toxicities after FEC100(5-fluorouracil 500mg/m2, epiru- bicin 100mg/m2, cyclophosphamide 500 mg/m2)chemotherapy for breast cancer. Granulocyte-colony stimulating factor(GCSF) is used as a support therapy for FN. Thus, we evaluated retrospectively the safety of administering pegfilgrastim the day after FEC100 chemotherapy in Japanese patients with breast cancer as compared with lenograstim. Grade 3 or 4 neutropenia was observed in 91.7% patients after pegfilgrastim administration and in 63.2% after lenograstim. The incidence rate of FN was 7.0%after pegfilgrastim administration and 9.7%after lenograstim, a difference that was not significantly different(p= 0.741). The mean relative dose intensity was good at 0.98 for pegfilgrastim and 0.97 for lenograstim. In conclusion, pegfilgrastim is not inferior to lenograstim in the incidence of FN. However, we do not recommend administering pegfilgrastim on the day after FEC100 therapy because it causes more severe neutropenia and has a high risk of FN. The timing of administration of pegfilgrastim in FEC100 therapy requires further study.
  • Masanobu Tsubaki; Daichiro Fujiwara; Tomoya Takeda; Toshiki Kino; Yoshika Tomonari; Tatsuki Itoh; Motohiro Imano; Takao Satou; Katsuhiko Sakaguchi; Shozo Nishida
    Clinical and experimental pharmacology & physiology 44 (2) 222 - 234 0305-1870 2017/02 [Refereed]
     
    Statins induce apoptosis of tumour cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanisms remain poorly understood. The present study showed that the induction of apoptosis by statins in four different human head and neck squamous cell carcinoma (HNSCC) cell lines, HSC-3, HEp-2, Ca9-22, and SAS cells was mediated by increased caspase-3 activity. Statins induced apoptosis by the suppression of geranylgeranyl pyrophosphate biosynthesis. Furthermore, statins decreased the levels of phosphorylated ERK and mTOR by inhibiting the membrane localization of Ras and enhancing Bim expression in HSC-3 and HEp-2 cells. We also found that in all the cell types analyzed, the IC50 values for fluvastatin and simvastatin were highest in HEp-2 cells. In addition, HSC-3, Ca9-22, and SAS cells had higher Ras expression and membrane localization, higher activation of ERK1/2 and mTOR, and lower levels of Bim expression than HEp-2 cells. Our results indicate that statins induce apoptosis by increasing the activation of caspase-3 and by enhancing Bim expression through inhibition of the Ras/ERK and Ras/mTOR pathways. Furthermore, the sensitivity of HNSCC cells to statin treatment was closely related to Ras expression and prenylation levels, indicating that statins may act more effectively against tumours with high Ras expression and Ras-variability. Therefore, our findings support the use of statins as potential anticancer agents.
  • Shozo Nishida; Masanobu Tsubaki
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan PHARMACEUTICAL SOC JAPAN 137 (2) 145 - 149 0031-6903 2017 [Refereed]
     
    Multidrug resistance (MDR) in cancer is a major problem in clinical settings: MDR correlates with a patient's poor prognosis and decreased quality of life. Recently, MDR was found to be involved in various signal pathways, so the inhibition of signal molecules by molecular targeting drugs may help overcome MDR. In addition, the acquisition of MDR is shown to be associated with the overexpression of drug efflux pumps such as P-glycoprotein (MDR1), which in turn affects the regulation of the expression of cell survival factors, B-cell leukemia protein 2 (Bcl-2) family proteins, etc. We analyzed the mechanisms of MDR in hematopoietic malignancies, and showed that the activation of signaling molecules regulated the expression of drug efflux pumps and cell survival factors, thus suggesting that molecular targeting drugs are potentially useful as anti-MDR agents. In this review, I focus on recent advancements in understanding the mechanisms of MDR with respect to hematopoietic malignancies: (1) exploration of molecular targets for overcoming MDR in anti-cancer drug-resistant cell lines, (2) the mechanism of drug resistance through the cytokine autocrine loop, and (3) cell-cell interaction with bone marrow stromal cells, along with the application of molecular targeting drugs for overcoming MDR.
  • Tomoya Takeda; Masanobu Tsubaki; Kotaro Sakamoto; Eri Ichimura; Aya Enomoto; Yuri Suzuki; Tatsuki Itoh; Motohiro Imano; Genzoh Tanabe; Osamu Muraoka; Hideaki Matsuda; Takao Satou; Shozo Nishida
    Toxicology and applied pharmacology 306 105 - 12 0041-008X 2016/09 [Refereed]
     
    Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa B kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma.
  • Masanobu Tsubaki; Tomoya Takeda; Misako Yoshizumi; Emi Ueda; Tatsuki Itoh; Motohiro Imano; Takao Satou; Shozo Nishida
    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37 (7) 9099 - 110 1010-4283 2016/07 [Refereed]
     
    Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells.
  • Tomoya Takeda; Masanobu Tsubaki; Toshiki Kino; Ayako Kawamura; Shota Isoyama; Tatsuki Itoh; Motohiro Imano; Genzoh Tanabe; Osamu Muraoka; Hideaki Matsuda; Takao Satou; Shozo Nishida
    International journal of oncology 48 (6) 2704 - 12 1791-2423 2016/06 [Refereed]
     
    Multiple myeloma (MM) is still an incurable hematological malignancy with a 5-year survival rate of ~35%, despite the use of various treatment options. The nuclear factor κB (NF-κB) pathway plays a crucial role in the pathogenesis of MM. Thus, inhibition of the NF-κB pathway is a potential target for the treatment of MM. In a previous study, we showed that mangiferin suppressed the nuclear translocation of NF-κB. However, the treatment of MM involves a combination of two or three drugs. In this study, we examined the effect of the combination of mangiferin and conventional anticancer drugs in an MM cell line. We showed that the combination of mangiferin and an anticancer drug decreased the viability of MM cell lines in comparison with each drug used separately. The decrease in the combination of mangiferin and an anticancer drug induced cell viability was attributed to increase the expression of p53 and Noxa and decreases the expression of XIAP, survivin, and Bcl-xL proteins via inhibition of NF-κB pathway. In addition, the combination treatment caused the induction of apoptosis, activation of caspase-3 and the accumulation of the cells in the sub-G1 phase of the cell cycle. Our findings suggest that the combination of mangiferin and an anticancer drug could be used as a new regime for the treatment of MM.
  • Tomoya Takeda; Masanobu Tsubaki; Toshiki Kino; Misa Yamagishi; Megumi Iida; Tatsuki Itoh; Motohiro Imano; Genzoh Tanabe; Osamu Muraoka; Takao Satou; Shozo Nishida
    Chemico-biological interactions 251 26 - 33 1872-7786 2016/05 [Refereed]
     
    Mangiferin is a naturally occurring glucosyl xanthone, which induces apoptosis in various cancer cells. However, the molecular mechanism underlying mangiferin-induced apoptosis has not been clarified thus far. Therefore, we examined the molecular mechanism underlying mangiferin-induced apoptosis in multiple myeloma (MM) cell lines. We found that mangiferin decreased the viability of MM cell lines in a concentration-dependent manner. We also observed an increased number of apoptotic cells, caspase-3 activation, and a decrease in the mitochondrial membrane potential. In addition, mangiferin inhibited the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated inhibitor kappa B (IκB) and increased the expression of IκB protein, whereas no changes were observed in the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase 1/2 (JNK1/2), and mammalian target of rapamycin (mTOR). The molecular mechanism responsible for mangiferin-induced inhibition of nuclear translocation of NF-κB was a decrease in the expression of phosphorylated NF-κB-inducing kinase (NIK). Moreover, mangiferin decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, and Bcl-xL proteins. Knockdown of NIK expression showed results similar to those observed with mangiferin treatment. Our results suggest that mangiferin induces apoptosis through the inhibition of nuclear translocation of NF-κB by suppressing NIK activation in MM cell lines. Our results provide a new insight into the molecular mechanism of mangiferin-induced apoptosis. Importantly, since the number of reported NIK inhibitors is limited, mangiferin, which targets NIK, may be a potential anticancer agent for the treatment of MM.
  • Masanobu Tsubaki; Kenji Mashimo; Tomoya Takeda; Toshiki Kino; Arisa Fujita; Tatsuki Itoh; Motohiro Imano; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 78 23 - 29 1950-6007 2016/03 [Refereed]
     
    Macrophage inflammatory protein-1alpha (MIP-1α) is detected at high concentrations in patients with multiple myeloma. It is thought to play an important role in the etiology of multiple myeloma and osteolysis. Thus, inhibiting MIP-1α expression may be useful in developing therapeutic treatments for multiple myeloma-induced osteolysis. In this study, we investigated the potential of statins to inhibit mRNA expression and secretion of MIP-1α in mouse myeloma cells (MOPC-31C). We found that statins inhibited the lipopolysaccharide (LPS)-induced MIP-1α mRNA expression and protein secretion in MOPC-31C cells. This inhibition was reversed when farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), intermediates of the mevalonate pathway, were combined with statins. Furthermore, statins reduced the GTP form of Ras, a phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated Akt. Our results indicate that statins inhibit biosynthesis of FPP and GGPP and thereby down regulate signal transduction of Ras/ERK and Ras/Akt pathways. The net effect suppresses LPS-induced MIP-1α mRNA expression and protein secretion in MOPC-31C cells. Thus, statins hold great promise for developing effective therapies against myeloma-induced osteolysis.
  • Hideyuki Mukai; Aiko Muramatsu; Rana Mashud; Koji Kubouchi; Sho Tsujimoto; Tsunaki Hongu; Yasunori Kanaho; Masanobu Tsubaki; Shozo Nishida; Go Shioi; Sally Danno; Mona Mehruba; Ryosuke Satoh; Reiko Sugiura
    Scientific reports NATURE PUBLISHING GROUP 6 18979 - 18979 2045-2322 2016/01 [Refereed]
     
    PKN, a conserved family member related to PKC, was the first protein kinase identified as a target of the small GTPase Rho. PKN is involved in various functions including cytoskeletal arrangement and cell adhesion. Furthermore, the enrichment of PKN3 mRNA in some cancer cell lines as well as its requirement in malignant prostate cell growth suggested its involvement in oncogenesis. Despite intensive research efforts, physiological as well as pathological roles of PKN3 in vivo remain elusive. Here, we generated mice with a targeted deletion of PKN3. The PKN3 knockout (KO) mice are viable and develop normally. However, the absence of PKN3 had an impact on angiogenesis as evidenced by marked suppressions of micro-vessel sprouting in ex vivo aortic ring assay and in vivo corneal pocket assay. Furthermore, the PKN3 KO mice exhibited an impaired lung metastasis of melanoma cells when administered from the tail vein. Importantly, PKN3 knock-down by small interfering RNA (siRNA) induced a glycosylation defect of cell-surface glycoproteins, including ICAM-1, integrin β1 and integrin α5 in HUVECs. Our data provide the first in vivo genetic demonstration that PKN3 plays critical roles in angiogenesis and tumor metastasis, and that defective maturation of cell surface glycoproteins might underlie these phenotypes.
  • Masanobu Tsubaki; Tomoya Takeda; Tadahumi Tani; Hirotaka Shimaoka; Naohiro Suzuyama; Kotaro Sakamoto; Arisa Fujita; Naoki Ogawa; Tatsuki Itoh; Motohiro Imano; Yoshinori Funakami; Seiji Ichida; Takao Satou; Shozo Nishida
    International journal of cancer WILEY-BLACKWELL 137 (1) 243 - 50 0020-7136 2015/07 [Refereed]
     
    Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy.
  • Ying-Feng Peng; Motohiro Imano; Tatsuki Itoh; Takao Satoh; Yasutaka Chiba; Haruhiko Imamoto; Masahiro Tsubaki; Shozo Nishida; Takushi Yasuda; Hiroshi Furukawa
    Journal of surgical oncology WILEY-BLACKWELL 111 (8) 1041 - 6 0022-4790 2015/06 [Refereed]
     
    BACKGROUND AND OBJECTIVES: We carried out a phase II trial to evaluate the feasibility, efficacy, and tolerability of perioperative chemotherapy including single intraperitoneal(IP) administration of paclitaxel(PTX) followed by intravenous(IV) administrations of PTX with S-1 in a neoadjuvant setting for serosa-positive gastric cancer. METHODS: Patients with cT4a gastric cancer were enrolled. A laparoscopic survey was performed before study inclusion for the confirmation of serosal invasion, negative lavage cytology, and negative peritoneal metastasis. IP PTX (80 mg/m(2)) was administered, followed by systemic chemotherapy. Surgery was performed after the completion of chemotherapy. The primary endpoint was the treatment completion rate. RESULTS: 37 patients were recruited. The treatment completion rate was 67.6% (25/37; 90% CI, 52.8-80.1%), which was significantly higher than 50%; we set this as a threshold value (P = 2.4% [one-sided]). 14 patients had target lesions; of these, 10 showed a partial response (71.4%), three had stable disease (21.4%), and one had progressive disease(7.2%). The response rate was 71.4% (10/14). All patients underwent gastrectomy with D2 lymph node dissection. The 3- and 5-year OS rates were 78.0 and 74.9%, respectively. CONCLUSIONS: Perioperative chemotherapy including neoadjuvant IP PTX followed by sequential IV PTX with S-1 for serosa-positive gastric cancer is feasible, safe, and efficient.
  • Masanobu Tsubaki; Tomoya Takeda; Naoki Ogawa; Kotaro Sakamoto; Hirotaka Shimaoka; Arisa Fujita; Tatsuki Itoh; Motohiro Imano; Toshihiko Ishizaka; Takao Satou; Shozo Nishida
    Leukemia research PERGAMON-ELSEVIER SCIENCE LTD 39 (4) 445 - 52 0145-2126 2015/04 [Refereed]
     
    The acquisition of anti-cancer drug resistance is a major limitation of chemotherapy for multiple myeloma (MM) and it is thus important to identify the mechanisms by which MM cells develop such drug resistance. In a previous study, we showed that multidrug resistance (MDR) involves the overexpression of MDR1 and survivin in vincristine-resistant RPMI8226/VCR cells. However, the underlying mechanism of MDR remains unclear. In this study, we investigated the mechanism of MDR in RPMI8226/VCR cells, and found that RPMI8226/VCR cells exhibit increased levels of activated ERK1/2, Akt, and NF-κB, while the levels of activated mTOR, p38MAPK, and JNK do not differ between RPMI8226/VCR cells and their vincristine-susceptible counterparts. In addition, the inhibition of ERK1/2, Akt, or NF-κB by inhibitors reversed the drug-resistance of RPMI8226/VCR cells via the suppression of survivin expression, but did not affect MDR1 expression; RNA silencing of survivin expression completely reversed vincristine resistance, while MDR1 silencing only weakly suppressed vincristine resistance in RPMI8226/VCR cells. These results indicate that enhanced survivin expression via the activation of ERK1/2, Akt, and NF-κB plays a critical role in vincristine resistance in RPMI8226/VCR cells. Our findings suggest that ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of vincristine-resistant MM.
  • Masanobu Tsubaki; Tomoya Takeda; Toshiki Kino; Naoya Obata; Tatsuki Itoh; Motohiro Imano; Kenji Mashimo; Daichiro Fujiwara; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida
    American journal of cancer research 5 (10) 3186 - 97 2156-6976 2015 [Refereed]
     
    Metastatic melanoma is a life-threatening disease for which no effective treatment is currently available. In melanoma cells, Rho overexpression promotes invasion and metastasis. However, the effect of statins on spontaneous metastasis and tumor growth remains unclear. In the present study, we investigated the mechanism of statin-mediated tumor growth and metastasis inhibition in an in vivo model. We found that statins significantly inhibited spontaneous metastasis and tumor growth. Statins inhibited the mRNA expression and enzymatic activities of matrix metalloproteinases (MMPs) in vivo and also suppressed the mRNA and protein expression of very late antigens (VLAs). Moreover, statins inhibited the prenylation of Rho as well as the phosphorylation of LIM kinase, serum response factor (SRF), and c-Fos downstream of the Rho signaling pathway. In addition, statins enhanced p53, p21, and p27 expression and reduced phosphorylation of cyclin-dependent kinase and expression of cyclin D1 and E2. These results indicate that statins suppress Rho signaling pathways, thereby inhibiting tumor metastasis and growth. Furthermore, statins markedly improved the survival rate in a metastasis model, suggesting that statins have potential clinical applications for the treatment of metastatic cancers.
  • Masanobu Tsubaki; Tomoya Takeda; Toshiki Kino; Tatsuki Itoh; Motohiro Imano; Genzo Tanabe; Osamu Muraoka; Takao Satou; Shozo Nishida
    American journal of translational research 7 (8) 1371 - 81 1943-8141 2015 [Refereed]
     
    Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of synovial joints, ultimately leading to a progressive and irreversible joint destruction. Activation of nuclear factor-kappa B (NF-κB) promotes production of proinflammatory cytokines in various inflammatory diseases including rheumatoid arthritis. Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside (C-glucosyl xanthone), is a naturally occurring polyphenol. Our previous results showed that mangiferin suppressed NF-κB activation. However, it is unclear, whether mangiferin can prevent rheumatoid arthritis through suppression of NF-κB activation and expression of various cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), which play a critical role in the pathogenesis of rheumatoid arthritis. In the present study, we found that mangiferin suppressed the progression and incidence of CIA in DBA1/J mice. In CIA mice, mangiferin inhibited the mRNA expression of cytokine genes in thymus and spleen of CIA mie and led to decreased serum levels of IL-1β, IL-6, TNF-α, and receptor activator NF-κB ligand (RANKL) via inhibition of NF-κB and activation of extracellular signal-regulated kinase 1/2 (ERK1/2). In addition, mangiferin markedly inhibited not only developing but also clinically evident CIA. These findings suggest that mangiferin has potential clinical applications for the treatment of rheumatoid arthritis.
  • Masanobu Tsubaki; Tomoya Takeda; Kotaro Sakamoto; Hirotaka Shimaoka; Arisa Fujita; Tatsuki Itoh; Motohiro Imano; Kenji Mashimo; Daiichiro Fujiwara; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida
    American journal of cancer research E-CENTURY PUBLISHING CORP 5 (1) 168 - 79 2156-6976 2015 [Refereed]
     
    Osteolytic bone disease in multiple myeloma (MM) is associated with upregulated osteoclast activity. Macrophage inflammatory protein-1α (MIP-1α) is crucially involved in the development of osteolytic bone lesions in MM. We previously reported that minodronate inhibited lipopolysaccharide-induced MIP-1α secretion in mouse myeloma cells. However, it remains unknown whether bisphosphonates and statins inhibit MIP-1α secretion by human MM cells. In present study, we investigated whether bisphosphonates and statins had any inhibitory effect on MIP-1α secretion by human myeloma cells and the mechanism underlying this effect. In this study, we found that bisphosphonates and statins inhibited MIP-1α mRNA and MIP-1α secretion and suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation by inhibiting Ras prenylation. Moreover, bisphosphonates and statins suppressed the expression of acute myeloid leukemia-1A (AML-1A) mRNA, a MIP-1α transcription factor. These results indicate that bisphosphonates and statins suppress the Ras/mitogen-activated protein kinase kinase/ERK/AML-1A and Ras/phosphatidylinositol-3 kinase/Akt/AML-1A pathways, thereby inhibiting MIP-1α secretion by MM cells. Therefore, use of MIP-1α expression inhibitors such as bisphosphonates and statins may provide a new therapeutic approach to inhibiting tumour progression and bone destruction in MM patients.
  • Masanobu Tsubaki; Naoki Ogawa; Tomoya Takeda; Kotaro Sakamoto; Hirotaka Shimaoka; Arisa Fujita; Tatsuki Itoh; Motohiro Imano; Takao Satou; Shozo Nishida
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER 68 (8) 999 - 1005 0753-3322 2014/10 [Refereed]
     
    Dimethyl fumarate (DMF) is a fumaric acid ester that is used to treat psoriasis and multiple sclerosis. Recently, DMF was found to exhibit anti-tumor effects. However, the molecular mechanisms underlying these effects have not been elucidated. In this study, we investigated the mechanism of DMF-induced apoptosis in different human hematopoietic tumor cell lines. We found that DMF induced apoptosis in different human hematopoietic tumor cell lines but it did not affect the normal human B lymphocyte cell line RPMI 1788. We also observed a concurrent increase in caspase-3 activity and in the number of Annexin-V-positive cells. Furthermore, an examination of the survival signals, which are activated by apoptotic stimuli, revealed that DMF significantly inhibited nuclear factor-κB (NF-κB) p65 nuclear translocation. In addition, DMF suppressed B-cell lymphoma extra-large (Bcl-xL) and X-linked inhibitor of apoptosis (XIAP) expression whereas Bcl-2, survivin, Bcl-2-associated X protein (Bax), and Bim levels did not change. These results indicated that DMF induced apoptosis by suppressing NF-κB activation, and Bcl-xL and XIAP expression. These findings suggested that DMF might have potential as an anticancer agent that could be used in combination therapy with other anticancer drugs for the treatment of human hematopoietic tumors.
  • Masanobu Tsubaki; Makiko Komai; Tatsuki Itoh; Motohiro Imano; Kotaro Sakamoto; Hirotaka Shimaoka; Tomoya Takeda; Naoki Ogawa; Kenji Mashimo; Daiichiro Fujiwara; Junji Mukai; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida
    Journal of biomedical science BIOMED CENTRAL LTD 21 (1) 10 - 10 1021-7770 2014/02 [Refereed]
     
    BACKGROUND: Bisphosphonates are an important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Recent studies have shown that nitrogen-containing bisphosphonates induced apoptosis in rabbit osteoclasts and prevented prenylated small GTPase. However, whether bisphosphonates inhibit osteoclast formation has not been determined. In the present study, we investigated the inhibitory effect of minodronate and alendronate on the osteoclast formation and clarified the mechanism involved in a mouse macrophage-like cell lines C7 and RAW264.7. RESULTS: It was found that minodronate and alendronate inhibited the osteoclast formation of C7 cells induced by receptor activator of NF-κB ligand and macrophage colony stimulating factor, which are inhibited by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. It was also found that minodronate and alendronate inhibited the osteoclast formation of RAW264.7 cells induced by receptor activator of NF-κB ligand. Furthermore, minodronate and alendornate decreased phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; similarly, U0126, a mitogen protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited osteoclast formation. CONCLUSIONS: This indicates that minodronate and alendronate inhibit GGPP biosynthesis in the mevalonate pathway and then signal transduction in the MEK/ERK and PI3K/Akt pathways, thereby inhibiting osteoclast formation. These results suggest a novel effect of bisphosphonates that could be effective in the treatment of bone metabolic diseases, such as osteoporosis.
  • Masanobu Tsubaki; Makiko Komai; Tatsuki Itoh; Motohiro Imano; Kotaro Sakamoto; Hirotaka Shimaoka; Tomoya Takeda; Naoki Ogawa; Kenji Mashimo; Daiichiro Fujiwara; Junji Mukai; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida
    Leukemia research PERGAMON-ELSEVIER SCIENCE LTD 38 (1) 121 - 30 0145-2126 2014/01 [Refereed]
     
    The calcium channel blocker verapamil inhibits the transport function of multidrug resistance protein 1 (MDR1). Although verapamil acts to reverse MDR in cancer cells, the underlying mechanism remains unclear. In the present study, we investigated the mechanism of reversing MDR by verapamil in anti-cancer drug-resistant multiple myeloma (MM) cell lines. We found that verapamil suppresses MDR1 and survivin expressions and increases Bim expression via suppression of Src activation. Furthermore, dasatinib reversed the drug-resistance of the drug-resistant cell lines. These findings suggest that Src inhibitors are potentially useful as an anti-MDR agent for the treatment of malignant tumor cells.
  • Motohiro Imano; Tatsuki Itoh; Takao Satou; Atsushi Yasuda; Kohei Nishiki; Hiroaki Kato; Osamu Shiraishi; Ying-Feng Peng; Masayuki Shinkai; Masahiro Tsubaki; Takushi Yasuda; Haruhiko Imamoto; Shozo Nishida; Yoshifumi Takeyama; Hiroshi Furkawa; Kiyokata Okuno; Hitoshi Shiozaki
    Targeted oncology 4 8 (4) 231 - 5 1776-2596 2013/12 [Refereed]
     
    Intraperitoneally administrated epithelial cellular adhesion molecule (EpCAM) monoclonal antibody is a therapeutic agent in patients with malignant effusion in several types of carcinoma. However, the role of EpCAM in peritoneal metastasis (PM) lesions and primary lesions of gastric cancer (GC) is still unclear. Therefore, in this study, we investigated EpCAM expression in GC patients with PM. We investigated the expression of EpCAM in 35PM lesions and 104 biopsy samples as primary lesions. Immunohistochemical staining was performed using the Ventana Benchmark XT (Roche Diagnostics) system. EpCAM expression was evaluated by calculating the total immunostaining score, which is the product of the proportion score and the intensity score. Overexpression was defined as a total score greater than 4. All PM specimens showed overexpression of EpCAM, and GC cells in both the surface layer and the deep layer of the PM showed a high expression of EpCAM. Meanwhile, in the biopsy sample, the expression of EpCAM ranged from none to strong. The EpCAM score results for PM specimens and biopsy samples were 11.0 ± 2.0 and 6.9 ± 3.9, respectively. The difference between the scores was statistically significant (P < 0.05). The intraperitoneally administrated EpCAM antibody might have a anti-cancer effect in PM lesions of GC. Additionally, it can be assumed that only GC cells which express a high level of EpCAM might metastasize to the peritoneum.
  • Masanobu Tsubaki; Makiko Komai; Tatsuki Itoh; Motohiro Imano; Kotaro Sakamoto; Hirotaka Shimaoka; Naoki Ogawa; Kenji Mashimo; Daichiro Fujiwara; Tomoya Takeda; Junji Mukai; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida
    European journal of cancer (Oxford, England : 1990) ELSEVIER SCI LTD 49 (17) 3708 - 17 0959-8049 2013/11 [Refereed]
     
    Several autocrine soluble factors, including macrophage inflammatory protein-1α and tumour necrosis factor-alpha (TNF-α), promote the survival and growth of multiple myeloma (MM) cells. We hypothesised that inhibition of the TNF-α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, a TNF-α-neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells. In addition, combination treatment with the TNF-α-neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor κB (NF-κB) p65 nuclear translocation and mammalian target of rapamycin (mTOR) activation and upregulated the expression of Bax and Bim. Treatment of ARH-77 cells with the NF-κB inhibitor dimethyl fumarate or the mTOR inhibitor rapamycin suppressed NF-κB p65 nuclear translocation and enhanced the cytotoxic effect of melphalan. Furthermore, infliximab, a monoclonal antibody against TNF-α, also enhanced the cytotoxic effect of anticancer drugs in ARH-77 cells. These results indicated that TNF-α-neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the TNF receptor/mTOR/NF-κB pathways. The inhibition of TNF-α may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients.
  • Masanobu Tsubaki; Makiko Komai; Shin-Ichiro Fujimoto; Tatsuki Itoh; Motohiro Imano; Kotaro Sakamoto; Hirotaka Shimaoka; Tomoya Takeda; Naoki Ogawa; Kenji Mashimo; Daiichiro Fujiwara; Junji Mukai; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida
    Journal of experimental & clinical cancer research : CR 1 32 (1) 62 - 62 1756-9966 2013/09 [Refereed]
     
    BACKGROUND: Increased motility and invasiveness of cancer cells are reminiscent of the epithelial-mesenchymal transition (EMT), which occurs during cancer progression and metastasis. Recent studies have indicated the expression of receptor activator of nuclear factor-κB (RANK) in various solid tumors, including breast cancer. Although activation of the RANK ligand (RANKL)/RANK system promotes cell migration, metastasis, and anchorage-independent growth of tumor-initiating cells, it remains to be investigated if RANKL induces EMT in breast cancer cells. In this study, we investigated whether RANKL induces EMT in normal breast mammary epithelial cells and breast cancer cells, and the mechanism underlying such induction. METHODS: Expression levels of vimentin, N-cadherin, E-cadherin, Snail, Slug, and Twist were examined by real-time polymerase chain reaction. Cell migration and invasion were assessed using Boyden chamber and invasion assays, respectively. The effects of RANKL on signal transduction molecules were determined by western blot analyses. RESULTS: We found that stimulation by RANKL altered the cell morphology to the mesenchymal phenotype in normal breast epithelial and breast cancer cells. In addition, RANKL increased the expression levels of vimentin, N-cadherin, Snail, and Twist and decreased the expression of E-cadherin. We also found that RANKL activated nuclear factor-κB (NF-κB), but not extracellular signal-regulated kinase 1/2, Akt, mammalian target of rapamycin, c-Jun N-terminal kinase, and signal transducer and activator of transcription 3. Moreover, dimethyl fumarate, a NF-κB inhibitor, inhibited RANKL-induced EMT, cell migration, and invasion, and upregulated the expressions of Snail, Twist, vimentin, and N-cadherin. CONCLUSIONS: The results indicate that RANKL induces EMT by activating the NF-κB pathway and enhancing Snail and Twist expression. These findings suggest that the RANKL/RANK system promotes tumor cell migration, invasion, and metastasis via the induction of EMT.
  • Tsubaki M; Komai M; Fujimoto S; Itoh T; Imano M; Sakamoto K; Shimaoka H; Takeda T; Ogawa N; Mashimo K; Fujiwara D; Mukai J; Sakaguchi K; Satou T; Nishida S
    Journal of experimental & clinical cancer research : CR 1 32 62  0392-9078 2013/09 [Refereed]
  • Tatsuki Itoh; Masaki Tabuchi; Nobuyuki Mizuguchi; Motohiro Imano; Masahiro Tsubaki; Shozo Nishida; Shigeo Hashimoto; Kazuhiko Matsuo; Takashi Nakayama; Akihiko Ito; Hiroshi Munakata; Takao Satou
    Journal of neural transmission (Vienna, Austria : 1996) SPRINGER WIEN 120 (5) 767 - 83 0300-9564 2013/05 [Refereed]
     
    Our previous study indicated that consuming (-)-epigallocatechin gallate (EGCG) before or after traumatic brain injury (TBI) eliminated free radical generation in rats, resulting in inhibition of neuronal degeneration and apoptotic death, and improvement of cognitive impairment. Here we investigated the effects of administering EGCG at various times pre- and post-TBI on cerebral function and morphology. Wistar rats were divided into five groups and were allowed access to (1) normal drinking water, (2) EGCG pre-TBI, (3) EGCG pre- and post-TBI, (4) EGCG post-TBI, and (5) sham-operated group with access to normal drinking water. TBI was induced with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3, and 7 days post-TBI, the number of 8-Hydroxy-2'-deoxyguanosine-, 4-Hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and levels of malondialdehyde around the damaged area were significantly decreased in all EGCG treatment groups compared with the water group (P < 0.05). Although there was a significant increase in the number of surviving neurons after TBI in each EGCG treatment group compared with the water group (P < 0.05), significant improvement of cognitive impairment after TBI was only observed in the groups with continuous and post-TBI access to EGCG (P < 0.05). These results indicate that EGCG inhibits free radical-induced neuronal degeneration and apoptotic death around the area damaged by TBI. Importantly, continuous and post-TBI access to EGCG improved cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.
  • Motohiro Imano; Tatsuki Itoh; Takao Satou; Akira Kido; Masahiro Tsubaki; Atsushi Yasuda; Hiroaki Kato; Haruhiko Imamoto; Shozo Nishida; Hiroshi Furukawa; Yoshifumi Takeyama; Kiyokata Okuno; Hitoshi Shiozaki
    Anticancer research INT INST ANTICANCER RESEARCH 33 (4) 1439 - 46 0250-7005 2013/04 [Refereed]
     
    AIM: Patients with scirrhous carcinoma of the gastrointestinal tract frequently develop peritoneal carcinomatosis-particularly of the peritoneal extension type (PET), which has a bad prognosis. We developed a novel animal model, suitable for testing treatments for PET. MATERIAL AND METHODS: In order to develop the model, we scraped the entire peritoneum of Fischer 344 rats with sterile cotton swabs and injected 1 × 10(6) cells of the RCN-9 cell type into the peritoneal cavity. RESULTS: In the novel experimental model, RCN-9 cells adhered only to the exposed basement membrane. The submesothelial layer and fibroblasts in the submesothelial layer grew and increased to a maximum at day 7, then decreased during late-phase peritoneal carcinomatosis. At day 14, RCN-9 cells coated the peritoneum in a manner similar to PET. CONCLUSION: We successfully established a novel animal model of peritoneal carcinomatosis that mimics clinicopathological features of PET. Fibroblasts in the submesothelial layer potentially play an important role in peritoneal carcinomatosis.
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Takashi Nakayama; Nobuyuki Mizuguchi; Shigeaki Yamanaka; Masaki Tabuchi; Hiroshi Munakata; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    Journal of neural transmission (Vienna, Austria : 1996) SPRINGER WIEN 120 (3) 361 - 74 0300-9564 2013/03 [Refereed]
     
    We have previously reported free radical production after traumatic brain injury (TBI), which induces neural stem cell (NSC) degeneration and death. However, the effects of aging on NSC proliferation around the damaged area following TBI have not been investigated. Therefore, in this study, we used 10-week (young group) and 24-month-old (aged group) rat TBI models to investigate the effects of aging on NSC proliferation around damaged tissue using immunohistochemical and ex vivo techniques. Young and aged rats received TBI. At 1, 3 and 7 days after TBI, immunohistochemical and lipid peroxidation studies were performed. Immunohistochemistry revealed that the number of nestin-positive cells around the damaged area after TBI in the aged group decreased significantly when compared with those in the young group (P < 0.01). However, the number of 8-hydroxy-2'-deoxyguanosine-, 4-hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells and the level of peroxidation around the damaged area after TBI significantly increased in the aged group, compared with those in the young group (P < 0.01). Furthermore, almost all ssDNA-positive cells in young and aged groups co-localized with NeuN and nestin staining. Ex vivo studies revealed that neurospheres, which differentiated into neurons and glia in culture, could only be isolated from injured brain tissue in young and aged groups at 3 days after TBI. These results indicate that, although there were fewer NSCs that have the potential to differentiate into neurons and glia, these NSCs escaped free radical-induced degeneration around the damaged area after TBI in the aged rat brain.
  • Masanobu Tsubaki; Tatsuki Itoh; Takao Satou; Motohiro Imano; Makiko Komai; Naoki Ogawa; Junji Mukai; Shozo Nishida
    Biochemical pharmacology PERGAMON-ELSEVIER SCIENCE LTD 85 (2) 163 - 72 0006-2952 2013/01 [Refereed]
     
    Nitrogen-containing bisphosphonates (N-BPs) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. The present study showed that the induction of apoptosis by N-BPs in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. Furthermore, N-BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression. The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways. The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors. This is the first study to show that the specific molecular pathways of N-BP-induced apoptosis.
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Nobuyuki Mizuguchi; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    Brain structure & function 1 218 (1) 209 - 20 1863-2653 2013/01 [Refereed]
     
    Progressive age-associated increases in cerebral dysfunction have been shown to occur following traumatic brain injury (TBI). Moreover, levels of neuronal mitochondrial antioxidant enzymes in the aged brain are reduced, resulting in free radical-induced cell death. It was hypothesized that cognitive impairment after TBI in the aged progresses to a greater degree than in younger individuals, and that damage involves neuronal degeneration and death by free radicals. In this study, we investigated the effects of free radicals on neuronal degeneration, cell death, and cognitive impairment in 10-week-old (young group) and 24-month-old rats (aged group) subjected to TBI. Young and aged rats received TBI with a pneumatic controlled injury device. At 1, 3 and 7 days after TBI, immunohistochemistry, lipid peroxidation and behavioral studies were performed. At 1, 3 and 7 days post-TBI, the number of 8-hydroxy-2'-deoxyguanosine-, 4-hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and the levels of malondialdehyde around the damaged area after TBI significantly increased in the aged group when compared with the young group (P < 0.05). In addition, the majority of ssDNA-positive cells in both groups co-localized with neuronal cells around the damaged area. There was a significant decrease in the number of surviving neurons and an increase in cognitive impairment after TBI in the aged group when compared with the young group (P < 0.05). These results indicate that following TBI, high levels of free radicals are produced in the aged rat brain, which induces neuronal degeneration and apoptotic cell death around the damaged area, resulting in cognitive impairment.
  • Motohiro Imano; Takao Satou; Tatsuki Itoh; Atsushi Yasuda; Hiroaki Kato; Masayuki Shinkai; Ying-Feng Peng; Masahiro Tsubaki; Takushi Yasuda; Haruhiko Imamoto; Shozo Nishida; Yoshifumi Takeyama; Kiyokata Okuno; Hitoshi Shiozaki
    Targeted oncology SPRINGER 7 (4) 213 - 6 1776-2596 2012/12 [Refereed]
     
    The prognosis of gastric cancer patients with peritoneal metastasis is very poor. Recent findings suggest that use of trastuzumab, a monoclonal antibody-based agent that targets human epidermal growth factor receptor 2 (HER2), may improve the prognosis of gastric cancer patients with HER2 overexpression and/or gene amplification. However, whether these mechanisms of HER2 upregulation are present in gastric cancer patients with peritoneal metastasis is unclear. The status of HER2 expression in a cohort of samples obtained from 35 gastric cancer patients with peritoneal metastasis was investigated using immunohistochemistry and fluorescence in situ hybridization. In 18 cases, we also investigated the influence of induction chemotherapy on HER2 overexpression. The frequency of HER2 overexpression and gene amplification was 2.9 % (1/35) in peritoneal metastatic lesions. There was concurrence in HER2 status in the samples examined prior to and following induction of chemotherapy. Most samples from the gastric cancer patients with peritoneal metastasis did not show HER2 amplification and/or overexpression. Although our study size was small, these results suggest that trastuzumab, which is critically dependent on HER2 expression, might not be an effective agent for these patients. Consequently, other therapeutic approaches for these patients must be developed.
  • Motohiro Imano; Atsushi Yasuda; Tatsuki Itoh; Takao Satou; Ying-Feng Peng; Hiroaki Kato; Masayuki Shinkai; Masahiro Tsubaki; Yasutaka Chiba; Takushi Yasuda; Haruhiko Imamoto; Shozo Nishida; Yoshifumi Takeyama; Kiyokata Okuno; Hiroshi Furukawa; Hitoshi Shiozaki
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract SPRINGER 16 (12) 2190 - 6 1091-255X 2012/12 [Refereed]
     
    BACKGROUND: We conducted a phase II study involving a single administration of intraperitoneal chemotherapy with paclitaxel followed by sequential systemic chemotherapy with S-1+ paclitaxel for advanced gastric cancer patients with peritoneal metastasis. METHODS: Gastric cancer patients with peritoneal metastasis were enrolled. Paclitaxel (80 mg/m(2)) was administered intraperitoneally at staging laparoscopy. Within 7 days, patients received systemic chemotherapy with S-1 (80 mg/m(2)/day on days 1-14) plus paclitaxel (50 mg/m(2) on days 1 and 8), followed by 7-days rest. The responders to this chemotherapy underwent second-look laparoscopy, and gastrectomy with D2 lymph node dissection was performed in patients when the disappearance of peritoneal metastasis had been confirmed. The primary endpoint of the study was overall survival rate. RESULTS: Thirty-five patients were enrolled. All patients were confirmed as having localized peritoneal metastasis by staging laparoscopy. Eventually, gastrectomy was performed in 22 patients. The median survival time of the total patient population and those patients in which gastrectomy was performed was 21.3 and 29.8 months, respectively. The overall response rate was 65.7 % for all patients. The frequent grade 3/4 toxic effects included neutropenia and leukopenia. CONCLUSIONS: Sequential intraperitoneal and intravenous paclitaxel plus S-1 was well tolerated in gastric cancer patients with peritoneal metastasis.
  • Masanobu Tsubaki; Takao Satou; Tatsuki Itoh; Motohiro Imano; Makiko Komai; Minori Nishinobo; Megumi Yamashita; Masashi Yanae; Yuzuru Yamazoe; Shozo Nishida
    Leukemia research PERGAMON-ELSEVIER SCIENCE LTD 36 (10) 1315 - 22 0145-2126 2012/10 [Refereed]
     
    Multidrug resistance represents a major obstacle for the chemotherapy of a wide variety of human tumors. To investigate the underlying mechanisms associated with resistance to anti-cancer drugs, we established anti-cancer drug-resistant multiple myeloma (MM) cell lines RPMI8226/ADM, RPMI8226/VCR, RPMI8226/DEX, and RPMI8226/L-PAM, the 50% inhibitory concentration values of which were 77-, 58-, 79-, and 30-fold higher than their parental cell lines, respectively. The resistant cell lines overexpressed MDR1 and survivin, or showed decreased Bim expression. These results indicated that regulating these factors with inhibitors might be a viable approach to increasing the susceptibility of quiescent MM cells to chemotherapy.
  • Masanobu Tsubaki; Takao Satou; Tatsuki Itoh; Motohiro Imano; Masashi Yanae; Chisato Kato; Risa Takagoshi; Makiko Komai; Shozo Nishida
    Molecular and cellular endocrinology ELSEVIER IRELAND LTD 361 (1-2) 219 - 31 0303-7207 2012/09 [Refereed]
     
    Osteoclast differentiation is influenced by receptor activator of the NF-κB ligand (RANKL), macrophage colony-stimulating factor (M-CSF), and CD9, which are expressed on bone marrow stromal cells and osteoblasts. In addition, osteoprotegerin (OPG) is known as an osteoclastogenesis inhibitory factor. In this study, we investigated whether bisphosphonates and statins increase OPG expression and inhibit the expression of CD9, M-CSF, and RANKL in the bone marrow-derived stromal cell line ST2. We found that bisphosphonates and statins enhanced OPG mRNA expression and inhibited the expression of CD9, M-CSF, and RANKL mRNA. Futhermore, bisphosphonates and statins decreased the membrane localization of Ras and phosphorylated ERK1/2, and activated the p38MAPK. This indicates that bisphosphonates and statins enhanced OPG expression, and inhibited the expression of CD9, M-CSF, and RANKL through blocking the Ras/ERK pathway and activating p38MAPK. Accordingly, we believe that its clinical applications will be investigated in the future for the development of osteoporosis therapy.
  • Motohiro Imano; Ying-Feng Peng; Tatsuki Itoh; Masayasu Nishikawa; Takao Satou; Atsushi Yasuda; Keisuke Inoue; Hiroaki Kato; Masayuki Shinkai; Masahiro Tsubaki; Takushi Yasuda; Haruhiko Imamoto; Shozo Nishida; Hiroshi Furukawa; Yoshifumi Takeyama; Kiyokata Okuno; Hitoshi Shiozaki
    Anticancer research INT INST ANTICANCER RESEARCH 32 (9) 4071 - 5 0250-7005 2012/09 [Refereed]
     
    AIM: A preliminary study with the aim of evaluating the safety and efficacy of a single intraperitoneal administration of paclitaxel, combined with intravenous administration of paclitaxel plus S-1, was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS: Paclitaxel was administered intraperitoneally at 80 mg/m(2). After one to two weeks, S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by seven days' rest. Paclitaxel was administered intravenously at 50 mg/m(2) on days 1 and 8. The safety, pharmacokinetic analysis and efficacy of this therapy were investigated. RESULTS: Fifteen patients were enrolled in this study. The toxic effects of the intraperitoneal chemotherapy were mild. The toxic effects with the systemic chemotherapy were acceptable. The ratio of (AUC peri)/(AUC pla) was 1065:1 in the pharmacokinetic analysis. The one-year overall survival rate was 10/15 (66.7%). CONCLUSION: A single intraperitoneal administration of paclitaxel combined with intravenous administration of paclitaxel plus S-1 is a well-tolerated and feasible treatment for patients with gastric cancer with peritoneal metastasis.
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Nobuyuki Mizuguchi; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    Journal of neural transmission (Vienna, Austria : 1996) SPRINGER WIEN 119 (8) 877 - 90 0300-9564 2012/08 [Refereed]
     
    A major component of green tea is (-)-epigallocatechin gallate (EGCG), which has strong antioxidant properties. Here, we investigated the effect of EGCG on neural stem cell (NSC) proliferation around the damaged area following traumatic brain injury (TBI). In this study, male Wistar rats that had access to normal drinking water, or water containing 0.1% (w/v) EGCG, ad libitum received TBI at 10 weeks of age. Immunohistochemistry revealed that the number of nestin-positive cells around the damaged area after TBI in the EGCG treatment group increased significantly compared with the normal water group (P < 0.05). However, the number of 8-hydroxy-2'-deoxyguanosine-, 4-hydroxy-2-nonenal-, single-stranded DNA (ssDNA)-positive cells and the level of peroxidation around the damaged area after TBI significantly decreased in the EGCG treatment group when compared with the water group (P < 0.05). Furthermore, in contrast to the EGCG group, almost all ssDNA-positive cells in the water group co-localized with NeuN and nestin-staining. Ex vivo studies revealed that spheres could only be isolated from injured brain tissue in the water group at 3 days following TBI. However, in the EGCG group, spheres could be isolated at both 3 and 7 days following TBI. A greater number of spheres could be isolated from the EGCG group, which differentiated into neurons and glia in culture without basic fibroblast growth factor. These results indicate that consumption of water containing EGCG pre- and post-TBI inhibits free radical-induced degradation of NSCs, which have the potential to differentiate into neurons and glia around the area of damage following TBI.
  • Masashi Yanae; Mariko Nakao; Kimiko Fujiwara; Akinori Kawaguchi; Masanobu Tsubaki; Yasutaka Chiba; Tetsuya Morita; Yuzuru Yamazoe; Shozo Nishida
    Gan to kagaku ryoho. Cancer & chemotherapy Japanese Journal of Cancer and Chemotherapy Publishers Inc. 39 (7) 1093 - 8 0385-0684 2012/07 [Refereed]
     
    Zoledronic acid(ZA)dosage should be adjusted according to the risk it poses for renal impairment. The recommended dosage for patients with creatinine clearance(Ccr)of less than 60mL/min was established on the basis of an area under the curve analysis, but is doubted because it was calculated without performing a clinical trial. Creatinine secretion from the renal tubule affects Ccr; therefore, using Ccr as the basis for dosage adjustment may be inappropriate since this can cause an overestimation of the glomerular filtration rate(GFR). The Japanese Society of Nephrology recommends using the estimated GFR(eGFR)for evaluating renal function. Therefore, this study investigated the relationship between renal function before and adverse events(AEs)after ZA administration. The dosage of only 3 of the 47 patients with Ccr less than 60mL/min could be adjusted on the basis of Ccr. During ZA therapy(3 courses), the blood urea nitrogen level and occurrence of hypokalemia were higher in the non-adjusted group than in the adjusted group, but the total number of AEs was equivalent for both groups. For all the patients, Ccr and eGFR were used as parameters for investigating AEs; the total number of AEs was equivalent for patients with differing levels of renal function. Therefore, we suggest that AEs observed during ZA therapy did not depend on the renal function level before ZA administration.
  • Masanobu Tsubaki; Takao Satou; Tatsuki Itoh; Motohiro Imano; Mitsuhiko Ogaki; Masashi Yanae; Shozo Nishida
    Toxicology and applied pharmacology ACADEMIC PRESS INC ELSEVIER SCIENCE 259 (3) 402 - 10 0041-008X 2012/03 [Refereed]
     
    Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Some patients continue to have a poor prognosis, because of the metastatic disease. YM529/ONO-5920 is a nitrogen-containing bisphosphonate that has been used for the treatment of osteoporosis. YM529/ONO-5920 has recently been reported to induce apoptosis in various tumors including osteosarcoma. However, the mode of metastasis suppression in osteosarcoma by YM529/ONO-5920 is unclear. In the present study, we investigated whether YM529/ONO-5920 inhibited tumor cell migration, invasion, adhesion, or metastasis in the LM8 mouse osteosarcoma cell line. We found that YM529/ONO-5920 significantly inhibited metastasis, cell migration, invasion, and adhesion at concentrations that did not have antiproliferative effects on LM8 cells. YM529/ONO-5920 also inhibited the mRNA expression and protein activities of matrix metalloproteinases (MMPs). In addition, YM529/ONO-5920 suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine protein kinase B (Akt) by the inhibition of Ras prenylation. Moreover, U0126, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, also inhibited LM8 cell migration, invasion, adhesion, and metastasis, as well as the mRNA expression and protein activities of MMP-1, MMP-2, MMP-9, and MT1-MMP. The results indicated that YM529/ONO-5920 suppressed the Ras/MEK/ERK and Ras/PI3K/Akt pathways, thereby inhibiting LM8 cell migration, invasion, adhesion, and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumor cell metastasis in osteosarcoma.
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    Stem Cells and Cancer Stem Cells, Volume 5: Therapeutic Applications in Disease and Injury Springer Netherlands 59 - 72 2012/01 [Refereed]
     
    Exercise enhances neuronal stem cell (NSC) proliferation and neurogenesis. However, the effect of exercise on NSC proliferationsurrounding the area of damage after traumatic brain injury (TBI) isunknown. Here, we investigate the effect of running on NSCproliferation following TBI in the rat. Wistar rats received TBI andwere randomly divided into two groups: (1) non-exercise group and(2) exercise group. The exercise group ran on a treadmill for 30min/day at 22 m/min for 7 consecutive days. Immunohistochemistry wasused to monitor NSC proliferation around the damaged area and ex vivo techniques were used to isolate NSCs from the damaged region in both groups. The number of nestin-and Ki-67-positive cells observed at 3 and 7 days after TBI was significantly greater in the exercise group than in the non-exercise group (P < 0.01). Furthermore, most nestin-positive cells in the exercise group co-localized with Ki-67-positive cells. In ex vivo studies, spheres could be isolated from injured brain tissue from the exercise group at 3 and 7 days following TBI, but at only 3 days in the non-exercise group. The number of spheres isolated from injured brain tissue was greater in the exercise group than in the non-exercise group. Spheres were immunopositive for nestin and comprised of NSCs that could differentiate into neurons and glia. Exercise increases the proliferation of NSCs around the damaged area following TBI. Therefore, exercise therapy (rehabilitation) in the early phase following TBI is important for recuperation from cerebral dysfunction induced by TBI.
  • Tatsuki Itoh; Kumiko Takemori; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Hiroyuki Ito; Akihiko Ito; Takao Satou
    Stem Cells and Cancer Stem Cells, Volume 2: Stem Cells and Cancer Stem Cells, Therapeutic Applications in Disease and Injury: Volume 2 Springer Netherlands 199 - 209 2012/01 [Refereed]
     
    Stroke-prone spontaneously hypertensive rats (SHRSP) are the only animal model that suffers from spontaneous cerebral stroke. In this study, we investigated the appearance of neural stem cells (NSCs) and new neurons in the penumbra and the subventricular zone (SVZ) after cerebral stroke in SHRSP. SHRSP before cerebral stroke were intraperitoneally injected with 5-bromo-2′-deoxyuridine (BrdU). SHRSP were divided into acute and chronic phase groups after cerebral stroke. Brain sections from both groups were studied with cellspecific markers such as BrdU, a cell division and proliferation marker, SOX2, a marker of NSCs, nestin, an NSC and immature astrocyte marker, doublecortin (DCX), an immature new neuron marker, and NeuN, a marker of mature neurons. NSCs and new neurons appeared in the penumbra in the early stages after cerebral stroke, and these cells differentiated into mature neurons in the chronic phase. Furthermore, soon after being affected by a cerebral stroke, there were many new neurons and immature cells, which appear to be NSCs, in the ipsilateral SVZ. The findings of the study indicate that immature cells and new neurons from the ipsilateral SVZ might migrate into the penumbra after cerebral stroke.
  • 柳江 正嗣; 椿 正寛; 中尾 真理子; 藤原 季美子; 浅野 肇; 森田 哲也; 山添 譲; 西田 升三
    ジェネリック研究 日本ジェネリック医薬品・バイオシミラー学会 5 (1) 58 - 64 1881-9117 2011/12 [Refereed]
     
    わが国では年々医療費が増大しており、患者負担の軽減および医療保険財政の改善を目的として後発医薬品(以下、後発品)の利用が推進されている。しかし、後発品に対する臨床試験は行われていないことから有効性や安全性の問題が指摘されているため、後発品での安全性の確立には臨床効果や有害事象発現状況を調査する必要がある。シスプラチン(以下、CDDP)はがん治療レジメンのキードラッグである。そのため、先発品と後発品での有害事象発現の差異が治療に影響する可能性が考えられることから、CDDP後発品の安全性を検討する必要がある。本検討では食道癌の標準レジメンであるCDDP+5FU療法でのCDDP先発品と後発品の有害事象発現状況の実態調査、特に腎関連事象について検討を行った。有害事象発現について比較検討した結果、血清クレアチニン(以下、CRE)上昇、しゃっくりの項目で後発品群に多く発現していた。患者背景では治療前BUNのみ後発品群で値の高い患者が多かった。BUNおよびCREの中央値の推移を検討した結果、BUN、CREともに先発品群と後発品群で差は認めなかった。またCDDP投与後のクレアチニンクリアランスおよびeGFRの推移では、先発品、後発品どちらの群においても同様の減少経緯を示した。以上の結果から後発品群による腎毒性は薬剤の性質の差異ではないと考えられた。またCDDPの重篤な有害事象である白血球減少や好中球減少の重症度に差は認められず、薬剤間の有害事象における特徴は同様であると考えられた。さらに2コース目の投与状況を調査した結果、両群で減量および中止された割合に有意な差を認めなかった。以上のことから、CDDP先発品と後発品での有害事象発現、特に重篤な副作用項目である腎機能障害に有意な差はなく、臨床上先発品と同様に使用できるものと示唆された。(著者抄録)
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    Neuromolecular medicine HUMANA PRESS INC 13 (4) 300 - 9 1535-1084 2011/12 [Refereed]
     
    A major component of green tea, a widely consumed beverage, is (-)-epigallocatechin gallate (EGCG), which has strong antioxidant properties. Our previous study has indicated that free radical production following rat traumatic brain injury (TBI) induces neural degeneration. In this study, we investigated the effects of EGCG on cerebral function and morphology following TBI. Six-week-old male Wistar rats that had access to normal drinking water, or water containing 0.1% (w/v) EGCG ad libitum, received TBI with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3 and 7 days post-TBI, the number of 8-hydroxy-2'-deoxyguanosine-, 4-hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and the levels of malondialdehyde (MDA) around the damaged area after TBI, significantly decreased in the EGCG treatment group compared with the water group (P < 0.05). Most ssDNA-positive cells in the water group co-localized with neuronal cells. However, in the EGCG treatment group, few ssDNA-positive cells co-localized with neurons. In addition, there was a significant increase in the number of surviving neuronal cells and an improvement in cerebral dysfunction after TBI in the EGCG treatment group compared with the water group (P < 0.05). These results indicate that consumption of water containing EGCG pre- and post-TBI inhibits free radical-induced neuronal degeneration and apoptotic cell death around the damaged area, resulting in the improvement of cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    Journal of neural transmission (Vienna, Austria : 1996) SPRINGER WIEN 118 (9) 1263 - 72 0300-9564 2011/09 [Refereed]
     
    Exercise is reported to inhibit neuronal apoptotic cell death in the hippocampus and improve learning and memory. However, the effect of exercise on inhibition of neuronal apoptosis surrounding the area of damage after traumatic brain injury (TBI) and the improvement of cerebral dysfunction following TBI are unknown. Here, we investigate the effect of exercise on morphology and cerebral function following TBI in rats. Wistar rats received TBI by a pneumatic controlled injury device were randomly divided into two groups: (1) non-exercise group and (2) exercise group. The exercise group ran on a treadmill for 30 min/day at 22 m/min for seven consecutive days. Immunohistochemical and behavioral studies were performed following TBI. The number of single-stranded DNA (ssDNA)-positive cells around the damaged area early after TBI was significantly reduced in the exercise group compared with the non-exercise group (P < 0.05). Furthermore, most ssDNA-positive cells in the non-exercise group co-localized with neuronal cells. However, in the exercise group, a few ssDNA-positive cells co-localized with neurons. In addition, there was a significant increase in neuronal cell number and improvement in cerebral dysfunction after TBI in the exercise group compared with the non-exercise group (P < 0.05). These results indicate that exercise following TBI inhibits neuronal degeneration and apoptotic cell death around the damaged area, which results in improvement of cerebral dysfunction. In summary, treadmill running improved cerebral dysfunction following TBI, indicating its potential as an effective clinical therapy. Therefore, exercise therapy (rehabilitation) in the early phase following TBI is important for recuperation from cerebral dysfunction.
  • Masashi Yanae; Masanobu Tsubaki; Takao Satou; Tatsuki Itoh; Motohiro Imano; Yuzuru Yamazoe; Shozo Nishida
    Journal of experimental & clinical cancer research : CR BIOMED CENTRAL LTD 30 74 - 74 1756-9966 2011/08 [Refereed]
     
    BACKGROUND: Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The inhibition of this key enzyme in the mevalonate pathway leads to suppression of cell proliferation and induction of apoptosis. However, the molecular mechanism of apoptosis induction by statins is not well understood in glioblastoma. In the present study, we attempted to elucidate the mechanism by which statins induce apoptosis in C6 glioma cells. METHODS: The cytotoxicity of statins toward the C6 glioma cells were evaluated using a cell viability assay. The enzyme activity of caspase-3 was determined using activity assay kits. The effects of statins on signal transduction molecules were determined by western blot analyses. RESULTS: We found that statins inhibited cell proliferation and induced apoptosis in these cells. We also observed an increase in caspase-3 activity. The apoptosis induced by statins was not inhibited by the addition of farnesyl pyrophosphate, squalene, ubiquinone, and isopentenyladenine, but by geranylgeranyl-pyrophosphate (GGPP). Furthermore, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. CONCLUSIONS: These results suggest that statins induce apoptosis when GGPP biosynthesis is inhibited and consequently decreases the level of phosphorylated ERK1/2 and Akt. The results of this study also indicate that statins could be used as anticancer agents in glioblastoma.
  • Yasuhiro Kidera; Masahiko Nakao; Masanobu Tsubaki; Masahiro Yoshinaga; Fumihiro Kajitani; Masashi Yanae; Mika Sakano; Yuzuru Yamazoe; Yasutaka Chiba; Kenzo Moriyama; Shozo Nishida
    Gan to kagaku ryoho. Cancer & chemotherapy Japanese Journal of Cancer and Chemotherapy Publishers Inc. 38 (7) 1143 - 8 0385-0684 2011/07 [Refereed]
     
    Glomerular filtration rate (GFR) is an important factor when considering carboplatin dosage adjustment. The Japanese equation for estimating GFR (eGFR) was recommended as a guideline for evaluating GFR in 2009 by The Japanese Society of Nephrology. However, benefits in the field of cancer chemotherapy with the use of eGFR have not yet been shown. To clarify the clinical benefits of eGFR, we investigated the renal function of 100 patients with gynecologic cancer who were treated with carboplatin from 2003 through 2009, and the carboplatin dosage was calculated by the Calvert formula in which eGFR was substituted for GFR. To predict the clinical benefit on the basis of carboplatin dosage using eGFR, we retrospectively divided the patients into two groups so that carboplatin dosage was within dosage in using eGFR and one was not. We compared response rates and adverse effects of the two groups. Renal function using eGFR was lower than renal function calculated by using the other formulae. Carboplatin dosage using eGFR was significantly lower than the dosage calculated with the other formulae (p<0.01). Moreover, the patients group actually, administered the dosage calculated by eGFR showed less side effects than the group of patients not treated this way, but the efficacy did not change. Thus, using eGFR in planning carboplatin dosage suggested clinical application to patients with Japanese gynecologic cancer.
  • Yasuhiro Kidera; Taroh Satoh; Shinya Ueda; Wataru Okamoto; Isamu Okamoto; Soichi Fumita; Kimio Yonesaka; Hidetoshi Hayashi; Chihiro Makimura; Kunio Okamoto; Hidemi Kiyota; Junji Tsurutani; Masaki Miyazaki; Masahiro Yoshinaga; Kimiko Fujiwara; Yuzuru Yamazoe; Kenzo Moriyama; Masanobu Tsubaki; Yasutaka Chiba; Shozo Nishida; Kazuhiko Nakagawa
    International journal of clinical oncology SPRINGER TOKYO 16 (3) 244 - 9 1341-9625 2011/06 [Refereed]
     
    BACKGROUND: Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective. METHODS: A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8 mg and granisetron 3 mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50 mg orally, followed by dexamethasone 20 mg, granisetron 3 mg, and famotidine 20 mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts. RESULTS: A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P = 0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2. CONCLUSION: Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned.
  • Masanobu Tsubaki; Yuzuru Yamazoe; Masashi Yanae; Takao Satou; Tatsuki Itoh; Junichi Kaneko; Yasuhiro Kidera; Kenzo Moriyama; Shozo Nishida
    Cytokine ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD 54 (1) 100 - 7 1043-4666 2011/04 [Refereed]
     
    The tumor microenvironment plays a critical role in modulating malignant behavior and can dramatically influence cancer treatment strategies. We investigated whether statins inhibit the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and transforming growth factor-β (TGF-β) mRNA in the mouse osteosarcoma cell line LM8. We found that statins significantly inhibited mRNA expressions of bFGF, HGF, and TGF-β, and bFGF, HGF, and TGF-β secretions at concentrations that did not have antiproliferative effects on LM8 cells, but had no effect on the mRNA expression and secretion of VEGF. The inhibition of bFGF, HGF, and TGF-β mRNA expression, and bFGF, HGF, TGF-β secretions was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination with statins. Furthermore, statins reduced the membrane localization of K-Ras, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated Akt. Our research indicates that statins inhibit GGPP biosynthesis in the mevalonate pathway, and then inhibit signal transduction in the Ras/ERK and Ras/Akt pathways, thereby inhibiting bFGF, HGF, TGF-β expression in LM8 cells. These results suggest that statins are potentially useful as anti-angiogenic agents for the treatment of osteosarcoma.
  • Kaori Shoji; Masanobu Tsubaki; Yuzuru Yamazoe; Takao Satou; Tatsuki Itoh; Yasuhiro Kidera; Yoshihiro Tanimori; Masashi Yanae; Hideaki Matsuda; Atsushi Taga; Haruyuki Nakamura; Shozo Nishida
    Archives of pharmacal research PHARMACEUTICAL SOC KOREA 34 (3) 469 - 75 0253-6269 2011/03 [Refereed]
     
    Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-β-D: -glucoside (C-glucosylxanthone), is a xanthone derivative that is widely distributed in higher plants. Recently, mangiferin was found to exhibit potential antitumor effects. However, the molecular mechanisms of this effect have not been elucidated. In the present study, we attempt to clarify the mechanism of mangiferin-induced apoptosis in the human acute myeloid leukemia cell line HL-60; mangiferin was found to induce apoptosis. We also observed a concurrent increase in caspase-3 activity and DNA fragmentation. Furthermore, on examining the survival signals expressed during apoptotic induction, we observed that mangiferin caused a remarkable decrease in the nuclear entry of NF-κB p65. However, there were no changes in the expression of other survival signals, such as extracellular signal-regulated kinase 1/2, protein kinase B, and p38 mitogenactivated protein kinase. In addition, mangiferin suppressed the expressions of Bcl-xL and XIAP; however, we did not note any changes in the levels of Bcl-2, Bax, and Bim. These results indicate that mangiferin induces apoptosis by suppressing NF-κB activation and expressions of Bcl-xL and XAIP. These findings suggest that mangiferin may be useful as an anticancer agent and can be used in combination therapy with other anticancer drugs for the treatment of acute myeloid leukemia.
  • Tatsuki Itoh; Motohiro Imano; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Akihiko Ito; Takao Satou
    Journal of neural transmission (Vienna, Austria : 1996) SPRINGER WIEN 118 (2) 193 - 202 0300-9564 2011/02 [Refereed]
     
    Exercise enhances neuronal stem cell (NSC) proliferation and neurogenesis. However, the effect of exercise on NSC proliferation surrounding the area of damage after traumatic brain injury (TBI) is unknown. Here, we investigate the effect of running on NSC proliferation following TBI in the rat. Wistar rats received TBI and were randomly divided into two groups: (1) non-exercise group and (2) exercise group. The exercise group ran on a treadmill for 30 min/day at 22 m/min for 7 consecutive days. Immunohistochemistry was used to monitor NSC proliferation around the damaged area, and ex vivo techniques were used to isolate NSCs from the damaged region in both groups. The number of nestin- and Ki67-positive cells observed at 3 and 7 days after TBI was significantly greater in the exercise group than in the non-exercise group (P < 0.01). Furthermore, most nestin-positive cells in the exercise group co-localized with Ki67-positive cells. In ex vivo studies, spheres could be isolated from injured brain tissue from the exercise group at 3 and 7 days following TBI, but at only 3 days in the non-exercise group. The number of spheres isolated from injured brain tissue was greater in the exercise group than in the non-exercise group. Spheres were immunopositive for nestin and comprised NSCs that could differentiate into neurons and glia. Exercise increases the proliferation of NSCs around the damaged area following TBI. Therefore, exercise therapy (rehabilitation) in the early phase following TBI is important for recuperation from cerebral dysfunction induced by TBI.
  • M Imano; H Imamoto; T Itoh; T Satou; Y F Peng; A Yasuda; H Kato; K Nishiki; O Shiraishi; M Shinkai; M Tsubaki; T Yasuda; S Nishida; Y Takeyama; K Okuno; H Shiozaki
    European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes KARGER 47 (4) 254 - 9 0014-312X 2011 [Refereed]
     
    BACKGROUND: There is no standard treatment available for gastric cancer patients whose sole 'non-curative factor' is positivecytological findings in peritoneal washings (CFPW). The aim of this study was to examine the safety, pharmacokinetics and efficacy for free intraperitoneal cancer cells of intraperitoneal chemotherapy with paclitaxel after gastrectomy with en bloc D2 lymph node dissection in cases of gastric cancer with positive CFPW. METHODS: Ten patients with gastric cancer who underwent gastrectomy and systemic lymphadenectomy with D2 dissection, without any other non-curative factors besides positive CFPW, were treated with early postoperative intraperitoneal paclitaxel. Intra-chemotherapeutic toxicity and operative complications were measured using NCI-CTC version 3.0. Intraperitoneal and plasma paclitaxel concentrations were measured using a high-performance liquid chromatographic assay. RESULTS: Grade 3/4 toxic effects included anemia (20%) and neutropenia (10%) that required no treatment. Operative complications were, for example, superficial surgical site infections (10%) that were treated with antibiotics. No viable cancer cells were observed in the intra-abdominal fluid 24 h after intraperitoneal administration of paclitaxel. The intraperitoneal/plasma area under the drug concentration-time curve ratio was 2,003.3:1. CONCLUSION: Intraperitoneal chemotherapy with paclitaxel is a safe and effective treatment modality for free intraperitoneal cancer cells.
  • Expression and Cerebral function of amyloid precursor protein after rat traumatic brain injury.
    Itoh T; Imano M; Nishida S; Tsubaki M; Hashimoto S; Ito A; Satou T
    Alzheimer's Disease pathogenesisi-core concepts, shifting paradigmas and therapeutic targets 31 - 52 2011 [Refereed]
  • Masanobu Tsubaki; Chisato Kato; Ai Isono; Junichi Kaneko; Misako Isozaki; Takao Satou; Tatsuki Itoh; Yasuhiro Kidera; Yoshihiro Tanimori; Masashi Yanae; Shozo Nishida
    Journal of cellular biochemistry WILEY-LISS 111 (6) 1661 - 72 0730-2312 2010/12 [Refereed]
     
    Multiple myeloma (MM) is a bone disease that affects many individuals. It was recently reported that macrophage inflammatory protein (MIP)-1α is constitutively secreted by MM cells. MIP-1α causes bone destruction through the formation of osteoclasts (OCs). However, the molecular mechanism underlying MIP-1α-induced OC formation is not well understood. In the present study, we attempted to clarify the mechanism whereby MIP-1α induces OC formation in a mouse macrophage-like cell line comprising C7 cells. We found that MIP-1α augmented OC formation in a concentration-dependent manner; moreover, it inhibited IFN-β and ISGF3γ mRNA expression, and IFN-β secretion. MIP-1α increased the expressions of phosphorylated ERK1/2 and c-Fos and decreased those of phosphorylated p38MAPK and IRF-3. We found that the MEK1/2 inhibitor U0126 inhibited OC formation by suppressing the MEK/ERK/c-Fos pathway. SB203580 induced OC formation by upregulating c-fos mRNA expression, and SB203580 was found to inhibit IFN-β and IRF-3 mRNA expressions. The results indicate that MIP-1α induces OC formation by activating and inhibiting the MEK/ERK/c-Fos and p38MAPK/IRF-3 pathways, respectively, and suppressing IFN-β expression. These findings may be useful in the development of an OC inhibitor that targets intracellular signaling factors.
  • Yasuhiro Kidera; Masanobu Tsubaki; Yuzuru Yamazoe; Kaori Shoji; Haruyuki Nakamura; Mitsuhiko Ogaki; Takao Satou; Tatsuki Itoh; Misako Isozaki; Junichi Kaneko; Yoshihiro Tanimori; Masashi Yanae; Shozo Nishida
    Journal of experimental & clinical cancer research : CR 29 (1) 127 - 127 1756-9966 2010/09 [Refereed]
     
    BACKGROUND: Melanomas are highly malignant and have high metastatic potential; hence, there is a need for new therapeutic strategies to prevent cell metastasis. In the present study, we investigated whether statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the B16BL6 mouse melanoma cell line. METHODS: The cytotoxicity of statins toward the B16BL6 cells were evaluated using a cell viability assay. As an experimental model, B16BL6 cells were intravenously injected into C57BL/6 mice. Cell migration and invasion were assessed using Boyden chamber assays. Cell adhesion analysis was performed using type I collagen-, type IV collagen-, fibronectin-, and laminin-coated plates. The mRNA levels, enzyme activities and protein levels of matrix metalloproteinases (MMPs) were determined using RT-PCR, activity assay kits, and Western blot analysis, respectively; the mRNA and protein levels of vary late antigens (VLAs) were also determined. The effects of statins on signal transduction molecules were determined by western blot analyses. RESULTS: We found that statins significantly inhibited lung metastasis, cell migration, invasion, and adhesion at concentrations that did not have cytotoxic effects on B16BL6 cells. Statins also inhibited the mRNA expressions and enzymatic activities of matrix metalloproteinases (MMPs). Moreover, they suppressed the mRNA and protein expressions of integrin α2, integrin α4, and integrin α5 and decreased the membrane localization of Rho, and phosphorylated LIM kinase (LIMK) and myosin light chain (MLC). CONCLUSIONS: The results indicated that statins suppressed the Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) pathways, thereby inhibiting B16BL6 cell migration, invasion, adhesion, and metastasis. Furthermore, they markedly inhibited clinically evident metastasis. Thus, these findings suggest that statins have potential clinical applications for the treatment of tumor cell metastasis.
  • 荘子 夏緒里; 大西 真理; 西嶌 昌子; 上村 秀樹; 尾垣 光彦; 杉本 由平; 椿 正寛; 西田 升三
    日本病院薬剤師会雑誌 (一社)日本病院薬剤師会 46 (5) 685 - 690 1341-8815 2010/05 [Refereed]
     
    がん患者やその家族が直面する問題は多種多様であり、包括的ケアを行う緩和ケアチーム(以下、PCT)の存在が必要となる。東大阪市立総合病院では2004年6月にPCTが発足し、2006年8月より多職種カンファレンスを開始したが経時的患者情報の把握が困難であった。そこで、情報共有のツールとしてPCTシートを構築した。また、同時に依頼表・計画書を改訂し、運用を改めた。2006年度、2007年度および2008年度を比較すると、依頼患者数は72人138人、238人診療加算算定回数は197回、805回、2,448回、入院からPCT介入までの平均期間は25.1日、17.3日、12.4日であった。よって、より多くの患者を対象にPCTの専門的ケアを提供できたと考える。また、依頼内容は身体症状の緩和に対する割合が各年度で多く、対応として薬物治療を必要とするため、薬剤師の存在意義が示唆された。(著者抄録)
  • Tatsuki Itoh; Takao Satou; Shozo Nishida; Masahiro Tsubaki; Motohiro Imano; Shigeo Hashimoto; Hiroyuki Ito
    Neurochemical research SPRINGER/PLENUM PUBLISHERS 35 (2) 348 - 55 0364-3190 2010/02 [Refereed]
     
    Edaravone is a novel free radical scavenger used clinically in patients with acute cerebral infarction; however, it has not been assessed in traumatic brain injury (TBI). We investigated the effects of edaravone on cerebral function and morphology following TBI. Rats received TBI with a pneumatic controlled injury device. Edaravone (3 mg/kg) or physiological saline was administered intravenously following TBI. Numbers of 8-OHdG-, 4-HNE-, and ssDNA-positive cells around the damaged area after TBI were significantly decreased in the edaravone group compared with the saline group (P < 0.01). There was a significant increase in neuronal cell number and improvement in cerebral dysfunction after TBI in the edaravone group compared with the saline group (P < 0.01). Edaravone administration following TBI inhibited free radical-induced neuronal degeneration and apoptotic cell death around the damaged area. In summary, edaravone treatment improved cerebral dysfunction following TBI, suggesting its potential as an effective clinical therapy.
  • Tatsuki Itoh; Takao Satou; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Hiroyuki Ito
    Neurotoxicity research SPRINGER 16 (4) 378 - 89 1029-8428 2009/11 [Refereed]
     
    Edaravone is a novel free radical scavenger that is clinically employed in patients with acute cerebral infarction, but has not previously been used to treat traumatic brain injury (TBI). In this study, we investigated the effect of edaravone administration on rat TBI. In particular, we used immunohistochemistry to monitor neural stem cell (NSC) proliferation around the area damaged by TBI. Two separate groups of rats were administered saline or edaravone (3 mg/kg) after TBI and then killed chronologically. We also used ex vivo techniques to isolate NSCs from the damaged region and observed nestin-positive cells at 1, 3, and 7 days following TBI in both saline- and edaravone-treated groups. At 3 days following TBI in both groups, there were many large cells that morphologically resembled astrocytes. At 1 and 7 days following TBI in the saline group, there were a few small nestin-positive cells. However, in the edaravone group, there were many large nestin-positive cells at 7 days following TBI. At 3 and 7 days following TBI, the number of nestin-positive cells in the edaravone group increased significantly compared with the saline group. There were many single-stranded DNA-, 8-hydroxy-2'-deoxyguanosine-, and 4-hydroxy-2-nonenal-positive cells in the saline group following TBI, but only a few such cells in the edaravone group following TBI. Furthermore, almost all ssDNA-positive cells in the saline group co-localized with Hu, nestin, and glial fibrillary acidic protein (GFAP) staining, but not in the edaravone group. In the ex vivo study, spheres could only be isolated from injured brain tissue in the saline group at 3 days following TBI. However, in the edaravone group, spheres could be isolated from injured brain tissue at both 3 and 7 days following TBI. The number of spheres isolated from injured brain tissue in the edaravone group showed a significant increase compared with the saline group. The spheres isolated from both saline and edaravone groups were immunopositive for nestin, but not Tuj1 or vimentin. Moreover, the spheres differentiated into Tuj1-, GFAP-, and O4-positive cells after 4 days in culture without bFGF. This result indicated that the spheres were neurospheres composed of NSCs that could differentiate into neurons and glia. Edaravone administration inhibited production of free radicals known to induce neuronal degeneration and cell death after brain injury, and protected nestin-positive cells, including NSCs, with the potential to differentiate into neurons and glia around the area damaged by TBI.
  • Yuzuru Yamazoe; Masanobu Tsubaki; Hiroshi Matsuoka; Takao Satou; Tatsuki Itoh; Takashi Kusunoki; Yasuhiro Kidera; Yoshihiro Tanimori; Kaori Shoji; Haruyuki Nakamura; Mitsuhiko Ogaki; Saori Nishiura; Shozo Nishida
    Cell biology international ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD 33 (10) 1087 - 94 1065-6995 2009/10 [Refereed]
     
    NF-kappaB acts as a signal transducer during tumor progression, cell invasion, and metastasis. Dimethylfumarate (DMF) is reported to inhibit tumor necrosis factor-alpha-induced nuclear entry of NF-kappaB/p65. However, only a few reports suggest that DMF inhibits tumor metastasis; also the molecular mechanisms underlying the inhibition of metastasis are poorly understood. We investigated the inhibition of tumor invasion and metastasis by DMF in a melanoma cell line, B16BL6. DMF inhibited B16BL6 cell invasion and metastasis by suppressing the expression and activities of MMPs. DMF also inhibited the nuclear entry of NF-kappaB/p65, thus inhibiting B16BL6 cell invasion and metastasis. These results suggest that DMF is potentially useful as an anti-metastatic agent for the treatment of malignant melanoma.
  • Hiroshi Matsuoka; Masanobu Tsubaki; Yuzuru Yamazoe; Mitsuhiko Ogaki; Takao Satou; Tatsuki Itoh; Takashi Kusunoki; Shozo Nishida
    Experimental cell research ELSEVIER INC 315 (12) 2022 - 32 0014-4827 2009/07 [Refereed]
     
    In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities of matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKCalpha and PKCdelta phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.
  • Tatsuki Itoh; Takao Satou; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Hiroyuki Ito
    Molecular and cellular biochemistry SPRINGER 324 (1-2) 191 - 9 0300-8177 2009/04 [Refereed]
     
    We previously demonstrated the increased amyloid precursor protein (APP) immunoreactivity around the site of damage after traumatic brain injury (TBI). However, the function of APP after TBI has not been evaluated. In this study, we investigated the effects of direct infusion of an anti-APP antibody into the damaged brain region on cerebral function and morphological changes following TBI in rats. Three days after TBI, there were many TUNEL-positive neurons and astrocytes around the damaged region and a significantly greater number of TUNEL-positive cells in the PBS group compared with the anti-APP group found. Seven days after TBI, there were significantly a greater number of large glial fibrillary acidic protein-positive cells, long elongated projections, and microtubule-associated protein-2-positive cells around the damaged region in the anti-APP group compared with the PBS group found. Seven days after TBI, the region of brain damage was significantly smaller and the time to arrival at a platform was significantly shorter in the anti-APP group compared with the PBS group. Furthermore, after TBI in the anti-APP group, the time to arrival at the platform recovered to that observed in uninjured sham operation group rats. These data suggest that the overproduction of APP after TBI inhibits astrocyte activity and reduces neural cell survival around the damaged brain region, which speculatively may be related to the induction of Alzheimer disease-type dementia after TBI.
  • Tatsuki Itoh; Takao Satou; Hiroyuki Ishida; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Hiroyuki Ito
    Neurological research MANEY PUBLISHING 31 (1) 90 - 102 0161-6412 2009/02 [Refereed]
     
    OBJECTIVE: The actual relationship between neural stem cells and SDF-1alpha/CXCR4 after brain injury has not yet been elucidated, although recent studies have speculated that stromal cell-derived factor-1alpha (SDF-1alpha) and its receptor, CXCR4, could contribute to neural stem cells migration after brain injury. In the present study, the temporal relationship between neural stem cells (NSCs) and SDF-1alpha/CXCR4 around a damaged area was investigated using a rat traumatic brain injury (TBI) model. METHODS: We used molecular biology techniques and immunohistochemistry to investigate the relationship between SDF-1alpha/CXCR4 expression and NSCs existence around a damaged area after TBI in the rat brain. RESULTS: SDF-1alpha mRNA expression and SDF-1alpha protein synthesis did not increase after TBI. However, SDF-1alpha leaked from the injured area and diffused into the cortex 1-3 days after TBI. Subsequently, the levels of CXCR4 mRNA expression and CXCR4 protein synthesis increased significantly. Many small cells with a nestin-positive cytoplasm and fibers also showed immunopositivity for both CXCR4 and SOX-2, but not for GFAP, 3-7 days after TBI. Moreover, a proportion of the CXCR4-positive cells and fibers also showed immunostaining for neurofilaments. DISCUSSION: These results suggest that the leaked SDF-1alpha attracted CXCR4-positive NSCs as well as elongated nerve fibers. It is considered that the SDF-1alpha/CXCR4 system in the brain contributes to neural stem cells appearance and maturation after TBI. Therefore, exploitation of the SDF-1alpha/CXCR4 system around a damaged area may improve the brain dysfunction after TBI.
  • Tatsuki Itoh; Takao Satou; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Hiroyuki Ito
    Neurological research MANEY PUBLISHING 31 (1) 103 - 9 0161-6412 2009/02 [Refereed]
     
    OBJECTIVE: Previous reports have demonstrated that some focal brain injuries increase amyloid precursor protein (APP) immunoreactivity in the region surrounding the injury in the cerebral cortex. However, the chronologic changes in APP expression have not been evaluated after traumatic brain injury (TBI). METHODS: In this study, we immunohistochemically and biologically investigated chronologic changes in cellular sources and levels of APP production after rat TBI. RESULTS: In the present report, we show that traumatic brain injury increased the expression of APP in the neuronal perikarya and in damaged dystrophic neurites from 1 to 90 days after injury. Moreover, 7 days after injury, some macrophages/microglia also were co-localized with APP, which was overproduced by the neuronal perikarya and APP-positive dystrophic neurites after injury and then APP were phagocytosed by macrophages/microglia during this phase. However, astroglia did not express APP immunopositivity after brain injury. DISCUSSION: These results suggested that long-term overexpression of APP was confirmed by immunohistochemical and biologic technique after TBI. This may be related to the induction of Alzheimer type dementia and it is a very important risk factor for this disease.
  • Tatsuki Itoh; Takao Satou; Shozo Nishida; Masahiro Tsubaki; Shigeo Hashimoto; Hiroyuki Ito
    Neurological research MANEY PUBLISHING 30 (4) 430 - 4 0161-6412 2008/05 [Refereed]
     
    OBJECTIVE: Protein-free extracts from the inflamed skin of rabbits inoculated with vaccinia virus (Rosemorgen and Neurotropin are widely employed to combat chronic pain and treat allergic conditions in human subjects in Japan. However, the pharmacologic mechanisms of Rosemorgen and Neurotropin remain unclear. METHODS: In this study, we examined the effects of Rosemorgen on L-glutamic acid (Glu)-induced cell death in N18-RE-105 neural cell line, which only possessed non-N-methyl-D-aspartate (NMDA)-type receptors. RESULTS: There were many large cytoplasmic cells and elongation of fivers in phosphate-buffered saline (PBS) additional group without Glu. In PBS and Glu simultaneous additional group, the survival ratio was decrease significantly compared with PBS alone group. Moreover, there were dead cells which did not have cytoplasm and aggregated nucleus. The Glu-induced cell death of N18-RE-105 cells was inhibited by both pre-treatment (24 hours before Glu treatment) and simultaneous treatment with Rosemorgen. There were many large cytoplasmic cells and elongation of fivers in Rosemorgen group. DISCUSSION: From this finding in N18-RE-105 cells, Rosemorgen was concluded to inhibit Glu-induced cell death via non-NMDA type receptors. One of the pharmacologic mechanisms of Rosemorgen has been clear. These results suggest that Rosemorgen depresses allodynia and chronic pain through interaction with non-NMDA type receptors.
  • Masanobu Tsubaki; Chisato Kato; Minori Nishinobo; Mitsuhiko Ogaki; Takao Satou; Tatsuki Ito; Takashi Kusunoki; Kimiko Fujiwara; Yuzuru Yamazoe; Shozo Nishida
    Cancer science BLACKWELL PUBLISHING 99 (1) 152 - 8 1347-9032 2008/01 [Refereed]
     
    Macrophage inflammatory protein 1 alpha (MIP-1 alpha) is detected at high concentrations in patients with multiple myeloma, and it is thought to play an important role in the etiology of multiple myeloma and osteolysis. Thus, we investigated whether or not YM529/ONO-5920, a new bisphosphonate, inhibited MIP-1 alpha mRNA expression in, and MIP-1 alpha secretion from, mouse myeloma cells. When the cells were stimulated by lipopolysaccharide, increased MIP-1 alpha mRNA expression and MIP-1 alpha secretion were observed. YM529/ONO-5920 inhibited MIP-1 alpha mRNA expression and MIP-1 alpha secretion in a concentration-dependent manner. A transient increase in the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) and Akt was observed after lipopolysaccharide stimulation. After YM529/ONO-5920 was given, there was no transient increase in the phosphorylation of ERK1/2 or Akt. These results indicated that YM529/ONO-5920 inhibited the expression and secretion of MIP-1 alpha through blocking the signaling pathway of the Ras/mitogen-activated protein kinase kinase/ERK and Ras/phosphatidylinositol-3 kinase/Akt. Accordingly, YM529/ONO-5920 appears to have promise for use in effective future therapy for osteolysis and myeloma cell growth that depends on MIP-1 alpha.
  • Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Saori Nishiura; Takeru Kawaguchi; Mitsuhiko Ogaki; Minori Nishinobo; Kenji Shimamoto; Kenzo Moriyama; Shozo Nishida
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan PHARMACEUTICAL SOC JAPAN 128 (1) 153 - 8 0031-6903 2008/01 [Refereed]
     
    Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, suppress cell proliferation and induce apoptosis in various cancer cell lines. However, the effects of statins in head and neck carcinoma have not been reported. In this study, we investigated the mechanism by which fluvastatin induces apoptosis in HSC-3 cells. An increase in caspase-3 activity was observed. The apoptosis induced by fluvastatin was inhibited by the addition of geranylgeranyl pyrophosphate (GGPP) to the cell culture. When we examined the survival signals at the time of apoptotic induction, we also found that fluvastatin had caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Moreover, we also found that U0126, a MEK1/2 inhibitor, induces apoptosis in HSC-3 cells. These results suggested that fluvastatin induces apoptosis by inhibiting GGPP biosynthesis and consequently decreasing the level of phosphorylated ERK1/2. The results of this study also indicate that fluvastatin may be used as an anticancer agent for tongue carcinoma.
  • Takeshi Kusunoki; Katsuhisa Ikeda; Kiyotaka Murata; Shozo Nishida; Masanobu Tsubaki
    Ear, nose, & throat journal VENDOME GROUP LLC 86 (12) 763 - 4 0145-5613 2007/12 [Refereed]
     
    Laryngeal plasmacytoma is rare in Japan; to the best of our knowledge, only 8 other cases have been previously reported. We report a new case of extramedullary plasmacytoma of the larynx in a 76-year-old Japanese woman. Immunohistochemical investigation revealed that her disease had not progressed to multiple myeloma. The patient declined radiotherapy, and her condition remained stable at the 6-month follow-up.
  • Masanobu Tsubaki; Chisato Kato; Miyuki Manno; Mitsuhiko Ogaki; Takao Satou; Tatsuki Itoh; Takashi Kusunoki; Yoshihiro Tanimori; Kimiko Fujiwara; Hiroshi Matsuoka; Shozo Nishida
    Molecular and cellular biochemistry SPRINGER 304 (1-2) 53 - 60 0300-8177 2007/10 [Refereed]
     
    Osteolytic lesions are rapidly progressive during the terminal stages of myeloma, and the bone pain or bone fracture that occurs at these lesions decreases the patients' quality of life to a notable degree. In relation to the etiology of this bone destruction, it has been reported recently that MIP-1alpha, produced in large amounts in myeloma patients, acts indirectly on osteoclastic precursor cells, and activates osteoclasts by way of bone-marrow stromal cells or osteoblasts, although the details of this process remain obscure. In the present study, our group investigated the mechanism by which RANKL expression is induced by MIP-1alpha and the effects of MIP-1alpha on the activation of osteoclasts. RANKL mRNA and RANKL protein expressions increased in both ST2 cells and MC3T3-E1 cells in a MIP-1alpha concentration-dependent manner. RANKL mRNA expression began to increase at 1 h after the addition of MIP-1alpha; the increase became remarkable at 2 h, and continuous expression was observed subsequently. Both ST2 and MC3T3-E1 cells showed similar levels of increased RANKL protein expression at 1, 2, and 3 days after the addition of MIP-1alpha. After the addition of MIP-1alpha, the amount of phosphorylated ERK1/2 and Akt protein expressions showed an increase, as compared to the corresponding amount in the control group. On the other hand, the amount of phosphorylated p38MAPK protein expression showed a decrease from the amount in the control group after the addition of MIP-1alpha. U0126 (a MEK1/2 inhibitor) or LY294002 (a PI3K inhibitor) was added to ST2 and MC3T3-E1 cells, and was found to inhibit RANKL mRNA and RANKL protein expression in these cells. When SB203580, a p38MAPK inhibitor, was added, RANKL mRNA and RANKL protein expression were increased in these cells. MIP-1alpha was found to promote osteoclastic differentiation of C7 cells, an osteoclastic precursor cell line, in a MIP-1alpha concentration-dependent manner. MIP-1alpha promoted differentiation into osteoclasts more extensively in C7 cells incubated together with ST2 and MC3T3-E1 cells than in C7 cells incubated alone. These results suggested that MIP-1alpha directly acts on the osteoclastic precursor cells and induces osteoclastic differentiation. This substance also indirectly induces osteoclastic differentiation through the promotion of RANKL expression in bone-marrow stromal cells and osteoblasts. The findings of this investigation suggested that activation of the MEK/ERK and the PI3K/Akt pathways and inhibition of p38MAPK pathway were involved in RANKL expression induced by MIP-1alpha in bone-marrow stromal cells and osteoblasts. This finding may be useful in the development of an osteoclastic inhibitor that targets intracellular signaling factors.
  • Masanobu Tsubaki; Hiroshi Matsuoka; Chikako Yamamoto; Chisato Kato; Mitsuhiko Ogaki; Takao Satou; Tatsuki Itoh; Takashi Kusunoki; Yoshihiro Tanimori; Shozo Nishida
    Clinical & experimental metastasis SPRINGER 24 (6) 431 - 8 0262-0898 2007 [Refereed]
     
    Protein kinase C (PKC) has been shown to be a signal transducer during tumorigenesis, tumor cell invasion, and metastasis. Recent studies have reported that the PKC inhibitor, 7-hydroxystaurosporine, inhibits tumor cell invasion. However, the molecular mechanisms of this inhibition of invasion and metastasis are not well understood. In the present study, we attempt to clarify the mechanism by which H7, a PKC inhibitor, inhibits tumor cell invasion and metastasis in the melanoma cell line B16BL6. It was found that H7 inhibits B16BL6 cell invasion and metastasis. We also observed that H7 inhibits the mRNA expression and protein activities of matrix metalloproteinase (MMP)-1, -2, -9 and MT1-MMP. Furthermore, H7 suppresses phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). However, other signal transduction factors, such as p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase 1/2 (JNK1/2), were unaffected. Moreover, U0126, a MEK1/2 inhibitor, also inhibited B16BL6 cell invasion and metastasis, as well as the mRNA expression and protein activities of MMP-1, -2, -9 and MT1-MMP. This indicates that H7 inhibits signal transduction through the PKC/MEK/ERK pathway, thereby inhibiting B16BL6 cell invasion and metastasis. These results suggest that PKC inhibitors have potential clinical applications in the treatment of tumor cell metastasis.
  • Shozo Nishida; Masanobu Tsubaki; Mayumi Hoshino; Ayumi Namimatsu; Hiromi Uji; Shohei Yoshioka; Yoshihiro Tanimori; Masashi Yanae; Masahiro Iwaki; Kiyohiro Irimajiri
    Biochemical and biophysical research communications ACADEMIC PRESS INC ELSEVIER SCIENCE 328 (1) 91 - 7 0006-291X 2005/03 [Refereed]
     
    Increase in bone resorption by osteoclasts can cause metabolic bone diseases, such as osteoporosis. Recent attention has been paid to the receptor activator of the NF-kappaB ligand (RANKL), an accelerator of osteoclast differentiation. RANKL is expressed on the bone marrow-derived stromal cell membrane and induces the differentiation of osteoclasts by binding to RANK expressed on the osteoclast precursor cell membrane. Since the inhibition of RANKL expression can lead to the inhibition of osteoclastic bone resorption, the clinical application of RANKL inhibition could be expected to have a major effect on metabolic bone disease therapy. In this study, we investigated whether or not YM529/ONO-5920, a nitrogen-containing bisphosphonate (a novel minodronic acid), inhibits RANKL expression in a bone marrow-derived stromal cell line (ST2 cells). Reverse transcription-polymerase chain reaction revealed that the administration of YM529/ONO-5920 to ST2 cells inhibited RANKL mRNA expression and reduced RANKL proteins as assessed by Western blot analysis. The inhibition of RANKL mRNA expression was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination. Furthermore, YM529/ONO-5920 reduced phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and similarly, U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, inhibited RANKL expression. Pretreatment with GGPP reversed the YM529/ONO-5920-induced decrease in phosphorylation of ERK. Furthermore, YM529/ONO-5920 decreased TRAP-positive cells in co-culture of ST2 cells and an osteoclast cell line, C7 cells, and this decrease was inhibited by pretreatment with GGPP. This indicates that YM529/ONO-5920 inhibits GGPP biosynthesis in the mevalonate pathway and then signal transduction in the Ras-mitogen-activated protein kinase pathway, thereby inhibiting RANKL expression on ST2 cells. These results suggest a newly elucidated action of bisphosphonates in the inhibition of bone resorption.
  • Shozo Nishida; Hiroshi Matsuoka; Masanobu Tsubaki; Yoshihiro Tanimori; Masasi Yanae; Yoshiki Fujii; Masahiro Iwaki
    Molecular and cellular biochemistry SPRINGER 269 (1-2) 109 - 14 0300-8177 2005/01 [Refereed]
     
    Mevastatin which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, suppress cell proliferation and induce apoptosis. However, the molecular mechanism of apoptosis induction is not well understood. So, in the present study, we attempted to clarify the mechanism by which mevastatin induces apoptosis in HL60 cells. It was found that mevastatin induced apoptosis. At that time, we observed an increase in caspase-3 activity and morphological fragmentation of the nuclei. The apoptosis induced by mevastatin was not inhibited by the addition of farnesyl pyrophosphate (FPP), squalene, ubiquinone, and isopentenyladenine, but was inhibited by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of mevastatin had caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals, such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38), exhibited no change. In addition, no quantitative change was observed in Bcl-2, which was an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggested that mevastatin induced apoptosis when it inhibited GGPP biosynthesis and consequently decreased the level of phosphorylated ERK, which was a survival signal; moreover, at that time, there was no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggested that mevastatin could be used as an anticancer agent.
  • Shozo Nishida; Shohei Yoshioka; Saori Kinoshita-Kimoto; Michiyo Kotani; Masanobu Tsubaki; Yoshiki Fujii; Takanori T Tomura; Kiyohiro Irimajiri
    Life sciences PERGAMON-ELSEVIER SCIENCE LTD 74 (6) 781 - 92 0024-3205 2003/12 [Refereed]
     
    Tumor necrosis factor alpha (TNF-alpha) modulates various events through several different pathways. Many tumor cells are resistant to this cytokine. Pretreatment of these cells with actinomycin D enhances TNF-alpha-induced apoptosis. In the present study, we investigated the mechanism of this enhancement and whether or not the apoptosis of TNF-alpha-resistant cancer cells can be induced by the inhibition of Protein kinase C (PKC). When TNF-alpha was added after inhibition of PKC by H7, apoptosis was observed, and companied with the activation of nuclear factor kappa B (NF-kappaB). After the inhibition of protein kinase B (Akt) by LY294002 or p38 mitogen-activated protein kinase (p38MAPK) by SB203580, the addition of TNF-alpha did not cause apoptosis. However, after the inhibition of MAPK/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) with U0126, apoptosis was observed when TNF-alpha was added. In the Western blotting analysis, phosphorylation of MEK1/2 occurred at 60 minutes after the addition of TNF-alpha. However, it was noted that after pretreatment with H7, a significant decrease in phosphorylated MEK1/2 was observed. The present findings suggest that MEK1/2 plays an important role in TNF-alpha-resistance in TNF-alpha-resistant B16 melanoma BL6 cells. Furthermore, it was found that MEK1/2 is more important than NF-kappaB, Akt, and p38MAPK in anti-apoptotic PKC signaling and that TNF-alpha-resistance can be overcome by inhibiting MEK1/2. These results suggest the possibility of development of a new anticancer drug treatment.
  • Shozo Nishida; Yoshiki Fujii; Shohei Yoshioka; Sigeru Kikuichi; Masanobu Tsubaki; Kiyohiro Irimajiri
    Life sciences PERGAMON-ELSEVIER SCIENCE LTD 73 (21) 2655 - 64 0024-3205 2003/10 [Refereed]
     
    It is believed that bisphosphonates (BPs) induce apoptosis in cells such as myeloma cells, as they inhibit prenylation of G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. In the present study, we attempted to clarify the mechanism by which YM529, a new bisphosphonate, induces apoptosis. YM529 induced cell deaths in HL60 cells in a concentration-dependent manner. At that time, we observed an increase in Caspase-3 activity and morphological fragmentation of the nuclei. We could confirm that these cell deaths were evidence of apoptosis. The apoptosis induced by YM529 was not inhibited by the addition of farnesyl pyrophosphate (FPP), but was by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of YM529 caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38) exhibited no change. In addition, no quantitative change was observed in Bcl-2, which is an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggest that YM529, the new bisphosphonate, induced apoptosis when inhibit GGPP synthase and consequently decreased the levels of phosphorylated ERK, which is a survival signal; moreover, during this process, there is no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggest that YM529 can be used as an anticancer agent, in addition to its use as a therapeutic agent to treat osteoporosis.
  • Shozo Nishida; Shigeru Kikuichi; Hisae Haga; Shohei Yoshioka; Masonobu Tsubaki; Katsuki Fujii; Kiyohiro Irimajiri
    Biological & pharmaceutical bulletin PHARMACEUTICAL SOC JAPAN 26 (1) 96 - 100 0918-6158 2003/01 [Refereed]
     
    In recent years, it has been reported that bisphosphonates inhibited the cell cycle of myeloma cells to inhibit cell proliferation directly, and it was also reported that bisphosphonates induced apoptosis of myeloma cells in vitro. Recently, YM529 was developed as a new third-generation bisphosphonate. In our experiment, we investigated whether YM529 showed an antitumor effect on hematopoietic tumor cell lines other than myeloma, and we compared YM529 with YM175, which had a relatively more potent antitumor effect than that of existing bisphosphonates. We found that YM529 inhibited cell proliferation in various hematopoietic tumor cell lines (acute promyelocytic leukemia cell line HL-60, chronic myeloid leukemia cell line K562, histiocytic lymphoma cell line U937, lymphoblastic leukemia T cell line Jurkat, acute lymphoblastic leukemia T cell line MOLT-4, lymphoblastic leukemia B cell line CCRF-SB) including myeloma (myeloma cell line HS-Sultan) dose-dependently and time-dependently to a degree equivalent or superior to that in myeloma, and induced apoptosis at a lower concentration as compared with YM175. We confirmed many dead cells as well as apoptosis based on the detection of the nuclei with separate globular structure, the activation of caspase-3, and the decrease in mitochondrial transmembrane potential. Therefore, it is concluded that further utilization of YM529 can be expected against hematopoietic tumor cells in the future.
  • S Nishida; S Kikuichi; S Yoshioka; M Tsubaki; Y Fujii; H Matsuda; M Kubo; K Irimajiri
    The American journal of Chinese medicine WORLD SCIENTIFIC PUBL CO PTE LTD 31 (4) 551 - 62 0192-415X 2003 [Refereed]
     
    In order to develop a new apoptosis inducer, we screened 22 crude drugs for their apoptosis-inducing activity. It was found that Glycyrrhiza uralensis, Cynomorium songaricum, Eucommia ulmoides, Phellodendron amurense, Cinnamomum cassia and Paeonia lactiflora induced the death of HL-60 cells. To investigate the mechanism of apoptosis induced by these six crude drugs, the mitochondrial transmembrane potential and the activity of caspase-3 were measured. Reduced mitochondrial transmembrane potentials within 12 hours after the administration of Glycyrrhiza uralensis, Cynomorium songaricum, Phellodendron amurense and Paeonia lactiflora, and within 24 hours after the administration of Eucommia ulmoides and Cinnamomum cassia were observed. All of the six apoptosis-inducing crude drugs increased caspase-3 activity within 12-36 hours after administration. After further examining the apoptosis-inducing activity of berberine, palmatine, panelofuroline and glycyrrhizin, which were the ingredients obtained from Phellodendron amurense, Glycyrrhiza uralensis and Paeonia lactiflora, it was found that only berberine could induce apoptosis. From these results, it was concluded that the apoptosis induced by the six crude drugs (Glycyrrhiza uralensis, Cynomorium songaricum, Eucommia ulmoides, Phellodendron amurense, Cinnamomum cassia and Paeonia lactiflora) occurred via the mitochondrial route and that the apoptosis-conducting mechanism acted through a cascade involving caspase-3.

Books etc

  • 岩崎, 克典; 徳山, 尚吾 南江堂 2018/03 9784524403356 xviii, 588p
  • Alzheimer's disease pathogenesis-core concepts, shifting paradigms and therapeutic targets, Expression and cerebral function of amyloid precursor protein after rat traumatic brain injury
    伊藤 龍生; 今野 元博; 西田 升三; 椿 正寛; 伊藤 彰彦; 佐藤 隆夫; 橋本 重夫 (Joint work)Intech open access publisher 2011/09 
    アルツハイマー病の老人斑を形成するβアミロイド蛋白の前駆体であるamyloid precursor protein(APP)は脳外傷により長期にわたり発現する。しかしながら脳外傷後におけるAPPの機能は不明な点が多い。そこで今回、我々はAPPの影響を検討するためにラット実験的脳損傷後の損傷部位に抗APP抗体を直接投与し、脳機能評価と形態学的変化を検討した。抗APP抗体投与により脳機能評価で有意な改善が認められた。抗APP抗体投与により損傷部位の面積に有意な減少を示した。抗APP抗体投与により多数の大型のアストロサイトとGFAP陽性面積の有意な増加が認められた。抗APP抗体投与によりMAP-2陽性細胞数が有意に増加した。これらのことから脳損傷後、APPが損傷周囲のアストロサイトや神経細胞に対して障害性に働くと考えられた。(英文）

Conference Activities & Talks

  • Statinsによる悪性黒色腫でのRho経路阻害を介した転移抑制・延命効果  [Not invited]
    坂本 洸太郎; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三
    日本薬学会第134回年会  2014/03
  • Nitrogen-containing bisphosphonatesによるRas/ERK及びRas/mTOR経路阻害を介したアポトーシス誘導機序  [Not invited]
    嶌岡 弘高; 椿 正寛; 駒居 真紀子; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三
    日本薬学会第134回年会  2014/03
  • 多発性骨髄腫での抗がん剤耐性獲得機序－シグナル伝達因子活性化によるMDR1、Survivin及びBimの発現調節－  [Not invited]
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三
    日本薬学会第134回年会  2014/03
  • 多発性骨髄腫でのTNF-αオートクライン阻害によるmTOR及びNF-κB抑制を介した抗がん剤感受性増強効果  [Not invited]
    椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三
    日本薬学会第134回年会  2014/03
  • 多発性骨髄腫における多剤耐性獲得機序の解明  [Not invited]
    駒居 真紀子; 椿 正寛; 坂本 洸太郎; 嶌岡 弘高; 小川 直希; 眞下 恵次; 藤原 大一郎; 向井 淳治; 阪口 勝彦; 山添 譲; 西田 升三
    第36回日本分子生物学会年会  2013/12
  • TNF-αオートクライン阻害による多発性骨髄腫での抗がん剤感受性増強効果  [Not invited]
    深松 真衣; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 向井 淳治; 阪口 勝彦; 西田 升三
    第63回日本薬学会近畿支部総会・大会  2013/10
  • Src阻害を介した多発性骨髄腫での抗がん剤耐性克服機序  [Not invited]
    小野 優里; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 向井 淳治; 阪口 勝彦; 西田 升三
    第63回日本薬学会近畿支部総会・大会  2013/10
  • NF-κB阻害剤での悪性黒色腫に対する抗腫瘍効果  [Not invited]
    辻 亜紀; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 向井 淳治; 阪口 勝彦; 西田 升三
    第63回日本薬学会近畿支部総会・大会  2013/10
  • StatinsによるRho/ROCK経路阻害を介した転移抑制効果  [Not invited]
    坂本 洸太郎; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 小川 直希; 眞下 恵次; 藤原 大一郎; 向井 淳治; 阪口 勝彦; 西田 升三
    第63回日本薬学会近畿支部総会・大会  2013/10
  • Bisphosphonatesによる造血器腫瘍でのRas経路阻害を介したアポトーシス誘導機序  [Not invited]
    嶌岡 弘高; 椿 正寛; 駒居 真紀子; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 向井 淳治; 阪口 勝彦; 西田 升三
    第63回日本薬学会近畿支部総会・大会  2013/10
  • 多発性骨髄腫でのシグナル伝達活性化を介した抗がん剤耐性獲得機序  [Not invited]
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 向井 淳治; 阪口 勝彦; 西田 升三
    第63回日本薬学会近畿支部総会・大会  2013/10
  • StatinsによるRho/LINK経路阻害を介した転移抑制効果  [Not invited]
    坂本 洸太郎; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三
    第72回日本癌学会学術総会  2013/10
  • TNF-alphaオートクライン阻害による抗がん剤殺細胞作用増強効果  [Not invited]
    西田 升三; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 阪口 勝彦; 向井 淳治
    第72回日本癌学会学術総会  2013/10
  • シグナル伝達因子活性化による多発性骨髄腫での抗がん剤耐性獲得機序  [Not invited]
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三
    第72回日本癌学会学術総会  2013/10
  • RANK/RANKLを介した抗がん剤耐性獲得機序  [Not invited]
    椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三
    第72回日本癌学会学術総会  2013/10
  • BisphosphonatesによるRas阻害を介した造血器腫瘍でのアポトーシス誘導  [Not invited]
    嶌岡 弘高; 椿 正寛; 駒居 真紀子; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三
    第72回日本癌学会学術総会  2013/10
  • TNF-αオートクライン阻害による抗がん剤感受性増強効果  [Not invited]
    西田 升三; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治
    第17回日本がん分子標的治療学会学術集会  2013/06
  • StatinsによるRho/ROCK/c-Fos経路阻害を介した転移抑制効果  [Not invited]
    坂本 洸太郎; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 西田 升三
    第17回日本がん分子標的治療学会学術集会  2013/06
  • 多発性骨髄腫でのシグナル伝達活性化を介した多剤耐性獲得機序  [Not invited]
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 西田 升三
    第17回日本がん分子標的治療学会学術集会  2013/06
  • BisphosphonatesによるRas経路阻害を介したBim発現増加でのアポトーシス誘導機序  [Not invited]
    嶌岡 弘高; 椿 正寛; 駒居 真紀子; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 西田 升三
    第17回日本がん分子標的治療学会学術集会  2013/06
  • RANK/RANKLによる多発性骨髄腫での抗がん剤耐性獲得機序  [Not invited]
    椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 西田 升三
    第17回日本がん分子標的治療学会学術集会  2013/06
  • 多発性骨髄腫の耐性に関与する因子の発現メカニズム  [Not invited]
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三
    第14回Pharmaco-Hematology Symposium  2013/06
  • 多発性骨髄腫における多剤耐性獲得因子の検討  [Not invited]
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一郎; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三
    第60回日本生化学会近畿支部例会  2013/05
  • Minodronateによる骨肉腫細胞でのRas経路阻害を介した転移抑制効果  [Not invited]
    嶌岡 弘高; 椿 正寛; 駒居 真紀子; 小川 直希; 山添 譲; 向井 淳治; 西田 升三
    日本薬学会第133回年会  2013/03
  • Bisphosphonatesおよびstatinsによる骨髄間質細胞でのOPG発現増強効果とその機序の解明  [Not invited]
    椿 正寛; 駒居 真紀子; 小川 直希; 山添 譲; 向井 淳治; 西田 升三
    日本薬学会第133回年会  2013/03
  • 多発性骨髄腫での抗がん剤多剤耐性獲得機序  [Not invited]
    駒居 真紀子; 椿 正寛; 小川 直希; 山添 譲; 向井 淳治; 西田 升三
    日本薬学会第133回年会  2013/03
  • NF-κB阻害剤による接着因子発現抑制を介した浸潤抑制効果  [Not invited]
    黒田梨江; 椿正寛; 駒居真紀子; 小川直希; 向井淳治; 西田升三
    第62回 日本薬学会近畿支部総会・大会  2012/10
  • NF-κB阻害剤による細胞死誘導効果とその機序の解明  [Not invited]
    木村沙織; 椿正寛; 駒居真紀子; 小川直希; 向井淳治; 西田升三
    第62回 日本薬学会近畿支部総会・大会  2012/10
  • NF-κB阻害剤による転移抑制効果  [Not invited]
    鈴木結理; 椿正寛; 駒居真紀子; 小川直希; 向井淳治; 西田升三
    第62回 日本薬学会近畿支部総会・大会  2012/10
  • 多発性骨髄腫における抗がん剤体積獲得機序  [Not invited]
    駒居真紀子; 椿正寛; 小川直希; 向井淳治; 西田升三
    第62回 日本薬学会近畿支部総会・大会  2012/10
  • Pioglitazone enhances the cytotoxic effects of anti-cancer drugs in head and neck carcinoma  [Not invited]
    Masanobu Tsubaki; Makiko Komai; Naoki Ogawa; Yuzuru Yamazoe; Junji Mukai; Shozo Nishida
    第71回 日本癌学会学術集会  2012/09
  • Reduction of metastasis in osteosarcoma by minodronic acid  [Not invited]
    Shozo Nishida; Masanobu Tsubaki; Makiko Komai; Naoki Ogawa; Yuzuru Yamazoe; Junji Mukai
    第71回 日本癌学会学術集会  2012/09
  • Overexpression of MDR1 and survivin, and decreased Bim expression mediate multidrug-resistance in multiple myeloma.  [Not invited]
    Makiko Komai; Masanobu Tsubaki; Naoki Ogawa; Yuzuru Yamazoe; Junji Mukai; Shozo Nishida
    第71回 日本癌学会学術集会  2012/09
  • Pioglitazoneによる抗がん剤殺細胞作用増強効果  [Not invited]
    椿 正寛; 駒居 真紀子; 小川 直希; 山添 譲; 向井 淳治; 西田 升三
    第16回 日本がん分子標的治療学会学術集会  2012/06
  • Minodronateによる骨肉腫細胞でのRas/MEK/ERK経路及びRas/PI3K/Akt経路阻害を介した転移抑制効果  [Not invited]
    西田 升三; 椿 正寛; 駒居 真紀子; 小川 直希; 山添 譲; 向井 淳治
    第16回日本がん分子標的治療学会学術集会  2012/06
  • MDR1及びsurvivinの過剰発現とBimの発現低下を介した多発性骨髄腫での多剤耐性獲得機序.  [Not invited]
    駒居 真紀子; 椿 正寛; 小川 直希; 山添 譲; 向井 淳治; 西田 升三
    第16回日本がん分子標的治療学会学術集会  2012/06
  • Statinsによる骨肉腫細胞での血管新生促進因子抑制効果  [Not invited]
    椿 正寛; 柳江 正嗣; 山添 譲; 松岡 寛; 西田 升三
    日本薬学会 第132年会  2012/03
  • Blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathways by statins reduces angiogenic factors in mouse osteosarcoma.  [Not invited]
    Masanobu Tsubaki; Masashi Yanae; Yasuhiro Kidera; Mitsuhiko Ogaki; Shozo Nishida
    第70回 日本癌学会学術総会  2011/09
  • Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits tumor metastasis in mouse melanoma  [Not invited]
    Shozo Nishida; Masanobu Tsubaki; Masashi Yanae; Yasuhiro Kidera; Mitsuhiko Ogaki
    第70回 日本癌学会学術総会  2011/09
  • StatinsによるRas/MEK/ERK及びRas/PI3K/Akt経路阻害を介した血管新生促進因子抑制効果  [Not invited]
    椿 正寛; 柳江 正嗣; 山添 譲; 松岡 寛; 西田 升三
    第15回 日本がん分子標的治療学会  2011/06
  • 骨髄腫分泌ケモカインMIP-1αによる破骨細胞分化促進効果  [Not invited]
    西田 升三; 椿 正寛; 柳江 正嗣; 山添 譲; 松岡 寛
    第15回 日本がん分子標的治療学会  2011/06
  • NF-κB inhibitor suppresses CIA by suppressing the expression of TNF-α and IL-6 and inhibiting the activation of NF-κB and ERK1/2.  [Not invited]
    Masanobu Tsubaki; Mitsuhiko Ogaki; Yasuhiro Kidera; Masashi Yanae; Kimiko Fujiwara; Shozo Nishida
    13th International TNF conference  2011/05
  • YM529/ONO-5920 によるマウス悪性黒色腫での浸潤、運動、接着、及び転移抑制効果  [Not invited]
    椿 正寛; 金子 淳一; 木寺 康裕; 柳江 正嗣; 岡本 龍治; 山添 譲; 西田 升三
    日本薬学会 第131年会  2011/03
  • Dimethylfumarate によるNF-kappaB 阻害を介した細胞浸潤および転移抑制効果  [Not invited]
    岡本 龍治; 椿 正寛; 金子 淳一; 山添 譲; 松岡 寛; 木寺 康裕; 柳江 正嗣; 西田 升三
    日本薬学会 第131年会  2011/03
  • Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits tumor metastasis in mouse melanoma through suppression of the Rho/ROCK pathway  [Not invited]
    Masanobu Tsubaki; Junichi Kaneko; Yasuhiro Kidera; Yoshihiro Tanimori; Masashi Yanae; Shozo Nishida
    第83回 日本生化学会大会  2010/12
  • NF-kappaB inhibitor suppresses tumor cell invasion and metastasis by inhibiting the expression and activaties of matrix metalloproteinases  [Not invited]
    Junichi Kaneko; Masanobu Tsubaki; Yuzuru Yamazoe; Yoshihiro Tanimori; Yasuhiro Kidera; Masashi Yanae; Shozo Nishida
    第83回 日本生化学会大会  2010/12
  • NF-κB阻害剤による多発性骨髄腫でのアポトーシス誘導効果及び機序の解明  [Not invited]
    西田 升三; 椿 正寛; 山岸 三紗; 金子 淳一
    第60回 日本薬学会近畿支部総会・大会  2010/10  大阪  第60回 日本薬学会近畿支部総会・大会
  • NF-κB阻害剤による悪性黒色腫での転移抑制効果及び機序の解明  [Not invited]
    西田 升三; 椿 正寛; 伊藤 弘二; 金子 淳一; 西川 恵里那; 松野 寛
    第60回 日本薬学会近畿支部総会・大会  2010/10  大阪  第60回 日本薬学会近畿支部総会・大会
  • Tamoxifen inhibits tumor metastasis through suppression of invasion and MMPs expression in mouse melanoma  [Not invited]
    Shozo Nishida; Junichi Kaneko; Masanobu Tsubaki; Hiroshi Matsuoka; Yasuhiro Kidera; Masashi Yanae; Yoshihiro Tanimori; Kimiko Fujiwaara; Kenzo Moriyama
    第69回 日本癌学会学術総会  2010/09
  • Dimethylfumarate inhibit lung metastasis through the suppression of NF-kappaB signaling.  [Not invited]
    Masanobu Tsubaki; Yuzuru Yamazoe; Hiroshi Matsuoka; Junichi Kaneko; Yasuhiro Kidera; Masashi Yanae; Yoshihiro Tanimori; Kimiko Fujiwara; Kenzo Moriyama; Shozo Nishida
    第69回日本癌学会学術総会  2010/09
  • StatinsによるRho/ROCK経路を介した肺転移抑制効果  [Not invited]
    椿 正寛; 山添 譲; 礒崎 美沙子; 礒野 藍; 金子 淳一; 尾垣 光彦; 荘子 夏緒里; 松岡 寛; 谷森 佳弘; 木寺 康裕; 柳江 正嗣; 西田 升三
    第14回 日本がん分子標的治療学会学術集会  2010/06
  • DimethylfumarateによるNF-kappaB阻害を介した肺転移抑制効果  [Not invited]
    金子 淳一; 椿 正寛; 山添 譲; 礒崎 美沙子; 礒野 藍; 松岡 寛; 谷森 佳弘; 木寺 康裕; 柳江 正嗣; 西田 升三
    第14回 日本がん分子標的治療学会学術集会  2010/06
  • マンギフェリンによる急性骨髄性白血病細胞におけるアポトーシス誘導機序の解明  [Not invited]
    椿 正寛; 礒野 藍; 礒崎 美沙子; 佐藤 健太郎; 金子 淳一; 荘子 夏緒里; 尾垣 光彦; 山添 譲; 木寺 康裕; 谷森 佳弘; 栁江 正嗣; 森山 健三; 松田 秀秋; 西田 升三
    日本薬学会 第130年会  2010/03
  • マンギフェリンによるHL-60細胞でのアポトーシス誘導効果  [Not invited]
    椿 正寛; 礒野 藍; 佐藤 健太郎; 金子 淳一; 松田 秀秋; 西田 升三
    第3回 食品薬学シンポジウム  2009/11
  • 新規ビスフォスフォネートYM529/ONO-5920でのMIP-1α分泌阻害効果  [Not invited]
    椿 正寛; 礒野 藍; 佐藤 健太郎; 金子 淳一; 木寺 康裕; 谷森 佳弘; 柳江 正嗣; 西田 升三
    第59回日本薬学会近畿支部総会・大会  2009/10
  • MIP-1αによる骨破壊促進機序の解明  [Not invited]
    礒野 藍; 椿 正寛; 佐藤 健太郎; 金子 淳一; 木寺 康裕; 谷森 佳弘; 柳江 正嗣; 西田 升三
    第59回日本薬学会近畿支部総会・大会  2009/10
  • タモキシフェンによる肺転移抑制効果  [Not invited]
    金子 淳一; 椿 正寛; 松岡 寛; 礒野 藍; 佐藤 健太郎; 木寺 康裕; 谷森 佳弘; 柳江 正嗣; 西田 升三
    第59回日本薬学会近畿支部総会・大会  2009/10
  • Macrophage inflammatory protein-1alpha induces osteoclast formation by activation of MEK/ERK pathway.  [Not invited]
    Shozo Nishida; Masanobu Tsubaki; Misako Isozaki; Ai Isono; Kentaro Sato; Junichi Kaneko; Yuzuru Yamazoe; Yasuhiro Kidera; Yoshihiro Tanimori
    第68回 日本癌学会学術総会  2009/09
  • Tamoxifen inhibits tumor metastasis through the suppression of PKC in mouse melanoma  [Not invited]
    Masanobu Tsubaki; Hiroshi Matsuoka; Misako Isozaki; Ai Isono; Kentaro Sato; Junichi Kaneko; Kaori Shoji; Mitsuhiko Ogaki; Haruyuki Nakamura; Masashi Yanae; Shozo Nishida
    第68回 日本癌学会学術総会  2009/09
  • タモキシフェンによるERKおよびAkt活性阻害を介した転移抑制効果  [Not invited]
    椿 正寛; 松岡 寛; 磯崎 美沙子; 礒野 藍; 佐藤 健太郎; 金子 淳一; 齋藤 裕介; 荘子 夏緒里; 尾垣 光彦; 中村 春行; 柳江 正嗣; 西田 升三
    第13回日本がん分子標的治療学会学術集会  2009/06
  • MIP-1alphaはMEK/ERK/c-Fos経路の活性化を介して破骨細胞形成を誘導する  [Not invited]
    西田 升三; 椿 正寛; 磯崎 美沙子; 礒野 藍; 佐藤 健太郎; 山添 譲; 谷森 佳弘; 木寺 康弘; 柳江 正嗣
    第13回日本がん分子標的治療学会学術集会  2009/06
  • PKC 阻害薬による接着阻害を介した転移抑制効果  [Not invited]
    椿 正寛; 松岡 寛; 礒崎 美沙子; 礒野 藍; 佐藤 健太郎; 山添 譲; 藤原 季美子; 谷森 佳弘; 木寺 康弘; 森山 健三; 中村 春行; 尾垣 光彦; 西田 升三
    日本薬学会 第129年会  2009/03
  • Protein kinase C inhibitor inhibited metastasis in mouse melanoma  [Not invited]
    Misako Isozaki; Masanobu Tsubaki; Minori Nishinobo; Ai Isono; Kantaro Sato; Kaori Shoji; Mitsuhiko Ogaki; Haruyuki Nakamura; Shozo Nishida
    第31回 日本分子生物学会年会 第81回 日本生化学会 合同大会  2008/12
  • MIP-1alpha increases a receptor activator of NF-kappaB ligand expression in bone marrow stromal cells and osteoblast.  [Not invited]
    Ai Isono; Masanobu Tsubaki; Minori Nishinobo; Misako Isozaki; Kentaro Sato; Yuzuru Yamazoe; Yasuhiro Kidera; Yoshihiro Tanimori; Kenzo Moriyama; Shozo Nishida
    第31回 日本分子生物学会年会 第81回 日本生化学会 合同大会  2008/12
  • Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma.  [Not invited]
    Masanobu Tsubaki; Minori Nishinobo; Misako Isozaki; Ai Isono; Kentaro Sato; Hrishi Matsuoka; Kaori Shoji; Mitsuhiko Ogaki; Haruyuki Nakamura; Shozo Nishida
    第31回 日本分子生物学会年会 第81回 日本生化学会 合同大会  2008/12
  • Nitrogen-containing bisphosphonates inhibits MIP-1alpha secretion in myeloma cell line  [Not invited]
    Minori Nishinobo; Masanobu Tsubaki; Ai Isono; Misako Isozaki; Kentaro Sato; Yuzuru Yamazoe; Yoshihiro Tanimori; Yasuhiro Kidera; Kenzo Moriyama; Shozo Nishida
    第31回 日本分子生物学会年会 第81回 日本生化学会 合同大会  2008/12
  • 新規ビスフォスフォネートYM529/ONO-5920によるMIP-1α分泌阻害を介した骨吸収抑制効果  [Not invited]
    西田 升三; 椿 正寛
    第11回 癌と骨病変研究会.  2008/11
  • Protein kinase C inhibitor inhibited metastasis through suppression of cell adhesion to type I and type IV collagen  [Not invited]
    Kentaro Sato; Masanobu Tsubaki; Minori Nishinobo; Ai Isono; Misako Isozaki; Kaori Shoji; Mitsuhiko Ogaki; Haruyuki Nakamura; Hiroshi Matsuoka; Shozo Nishida
    第67回 日本癌学会学術総会  2008/09
  • PKC inhibitor suppresses tumor cell invasion in mouse melanoma cells  [Not invited]
    Misako Isozaki; Masanobu Tsubaki; Minori Nishinobo; Ai Isono; Kentaro Sato; Kaori Shoji; Mitsuhiko Ogaki; Haruyuki Nakamura; Hiroshi Matsuoka; Shozo Nishida
    第67回 日本癌学会学術総会  2008/09
  • MIP-1alpha increases a RANKL expression in bone marrow stromal cells and osteoblasts through MAPK and PI3K/Akt pathway  [Not invited]
    Ai Isono; Masanobu Tsubaki; Minori Nishinobo; Misako Isozaki; Kentaro Sato; Yuzuru Yamazoe; Yasuhiro Kidera; Yoshihiro Tanimori; Kenzo Moriyama; Shozo Nishida
    第67回 日本癌学会学術総会  2008/09
  • Statins induces apoptpsis in various tumor cells dependently on inhibition by Ras/MEK/ERK pathway  [Not invited]
    Masanobu Tsubaki; Minori Nishinobo; Ai Isono; Misako Isozaki; Kentaro Sato; Yuzuru Yamazoe; Yoshihiro Tanimori; Yasuhiro Kidera; Kenzo Moriyama; Shozo Nishida
    第67回 日本癌学会学術総会  2008/09
  • Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits MIP-1alpha secretion in myeloma cells.  [Not invited]
    Minori Nishinobo; Masanobu Tsubaki; Ai Isono; Misako Isozaki; Kentaro Sato; Yuzuru Yamazoe; Yoshihiro Tanimori; Yasuhiro Kidera; Kenzo Moriyama; Shozo Nishida
    第67回 日本癌学会学術総会  2008/09
  • PKC阻害薬によるERK1/2活性低下を介した悪性黒色腫細胞株B16BL6細胞の肺転移抑制効果  [Not invited]
    椿 正寛; 西之坊 実里; 尾垣 光彦; 山添 譲; 松岡 寛; 荘子 夏緒里; 中村 春行; 西田 升三
    第12回 がん分子標的治療研究会総会  2008/06
  • 新規ビスフォスフォネートYM529でのRasゲラニルゲラニル化阻害を介したMIP-1alpha分泌阻害効果  [Not invited]
    Shozo Nishida; Masanobu Tsubaki; Minori Nishinobo; Mitsuhiko Ogaki; Misako Isozaki; Ai Isono; Hiroshi Matsuoka; Yuzuru Yamazoe; Yoshihiro Tanimori; Yasuhiro Kidera
    第12回日本がん分子標的治療研究会総会  2008/06
  • MIP-1alphaによる骨髄間質細胞および骨芽細胞におけるRANKL発現促進効果を介した骨破壊機序の解明  [Not invited]
    Minori Nishinobo; Masanobu Tsubaki; Ai Isono; Misako Isozaki; Kentaro Sato; Yuzuru Yamazoe; Toshihiro Tanimori; Yasyhiro Kidera; Kenzo Moriyama; Shozo Nishida
    第12回日本がん分子標的治療研究会総会  2008/06
  • MIP-1αによるRANKL発現促進効果およびその機序の解明.  [Not invited]
    椿 正寛; 西之坊 実里; 尾垣 光彦; 山添 譲; 松岡 寛; 荘子 夏緒里; 中村 春行; 西田 升三
    日本薬学会 第128年会  2008/03
  • Protein kinase C inhibitor inhibited pulmonary metastasis in mouse melanoma through suppression of cell adhesion to type I collagen  [Not invited]
    Masanobu Tsubaki; Mitsuhiko Ogaki; Minori Nishinobo; Yuzuru Yamazoe; Kimiko Fujiwara; Hiroshi Matsuoka; Saori Nishiura; Shozo Nishida
    第30回日本分子生物学会年会 第80回日本生化学会 合同大会  2007/12
  • PKC inhibitor, H7, inhibited tumor cell invasion and metastasis.  [Not invited]
    Mitsuhiko Ogaki; Masanobu Tsubaki; Minori Nishinobo; Yuzuru Yamazoe; Kimiko Fujiwara; Hiroshi Matsuoka; Saori Nishiura; Shozo Nishida
    第30回日本分子生物学会年会 第80回日本生化学会 合同大会  2007/12
  • Macrophage inflammatory protein-1alpha (MIP-1alpha) enhances a receptor activator of nuclear factor kappaB ligand (RANKL) expression in mouse bone marrow stromal cells and osteoblasts.  [Not invited]
    Minori Nishinobo; Masanobu Tsubaki; Mitsuhiko Ogaki; Yuzuru Yamazoe; Kimiko Fujiwara; Hiroshi Matsuoka; Saori Nishiura; Shozo Nishida
    第30回日本分子生物学会年会 第80回日本生化学会 合同大会  2007/12
  • Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK1/2  [Not invited]
    Minori Nishinobo; Masanobu Tsubaki; Mitsuhiko Ogaki; Kimiko Fujiwara; Yuzuru Yamazoe; Kenzo Moriyama; Shozo Nishida
    第66回 日本癌学会学術総会  2007/10
  • A novel bisphosphonate, YM529, induces apoptosis in HL60 cells dependent on decrease in phosphorylated ERK1/2  [Not invited]
    Kimiko Fujiwara; Masanobu Tsubaki; Mitsuhiko Ogaki; Minori Nishinobo; Yuzuru Yamazoe; Kenzo Moriyama; Shozo Nishida
    第66回 日本癌学会学術総会  2007/10
  • Protein kinase C inhibitor, H7, inhibits lung metastasis in mouse melanoma through suppression of cell adhesion  [Not invited]
    Masanobu Tsubaki; Mitsuhiko Ogaki; Minori Nishinobo; Kimiko Fujiwara; Yuzuru Yamazoe; Kenzo Moriyama; Shozo Nishida
    第66回 日本癌学会学術総会  2007/10
  • The PKC inhibitor, H7, inhibits tumor cell invasion and metastasis through the suppression of ERK1/2 activation  [Not invited]
    Mitsuhiko Ogaki; Masanobu Tsubaki; Minori Nishinobo; Kimiko Fujiwara; Yuzuru Yamazoe; Kenzo Moriyama; Shozo Nishida
    第66回 日本癌学会学術総会  2007/10
  • HMG-CoA還元酵素阻害剤(statins)によるRas-ERK1/2経路阻害を介したアポトーシス誘導  [Not invited]
    尾垣 光彦; 椿 正寛; 加藤 知里; 谷森 佳弘; 柳江 正嗣; 西田 升三
    第11回 がん分子標的治療研究会総会  2007/06
  • C kinase 阻害剤によるERK1/2活性低下を介した悪性黒色腫細胞株B16BL6細胞の浸潤抑制効果  [Not invited]
    椿 正寛; 尾垣 光彦; 加藤 知里; 谷森 佳弘; 松岡 寛; 西田 升三
    第11回 がん分子標的治療研究会総会  2007/06
  • 新規ビスフォスフォネートYM529でのRasゲラニルゲラニル化阻害を介したRANKL発現阻害効果  [Not invited]
    西田 升三; 加藤 知里; 椿 正寛; 尾垣 光彦; 山添 譲
    第11回 がん分子標的治療研究会総会  2007/06
  • 新規bisphosphonate系薬剤YM529における骨髄間質細胞でのRANKL発現阻害効果  [Not invited]
    西田 升三; 椿 正寛; 加藤 知里; 尾垣 光彦; 谷森 佳弘; 柳江 正嗣; 入交 清博
    日本薬学会 第127年会  2007/03
  • PKC阻害薬によるMMPs分泌阻害でのがん細胞浸潤抑制効果  [Not invited]
    椿 正寛; 尾垣 光彦; 加藤 知里; 谷森 佳弘; 柳江 正嗣; 西田 升三
    日本薬学会 第127年会  2007/03
  • 新規bisphosphonate系薬剤YM529におけるRANKL発現阻害によるがん細胞の骨髄内増殖および骨融解の抑制  [Not invited]
    西田升三; 加藤知里; 椿 正寛; 尾垣光彦; 谷森佳弘; 栁江正嗣; 入交清博
    第65回 日本癌学会学術総会  2006/10
  • Protein kinase C阻害によるがん細胞の浸潤抑制効果  [Not invited]
    椿 正寛; 尾垣光彦; 加藤知里; 谷森佳弘; 栁江正嗣; 西田升三
    第65回 日本癌学会学術総会  2006/10
  • HMG-CoA還元酵素阻害薬であるstatinのアポトーシス誘導機序の解明  [Not invited]
    戸村隆訓; 椿 正寛; 加藤知里; 尾垣光彦; 藤井克樹; 谷森佳弘; 柳江正嗣; 西田升三
    第65回 日本癌学会学術総会  2006/10
  • Nitrogen-containing bisphosphonate, YM529 (a novel minodronic acid), inhibits RANKL expression in bone marrow stromal cells  [Not invited]
    Masanobu Tsubaki; Mayumi Hoshino; Ayumi Namimatsu; Hiromi Uji; Masashi Yanae; Chisato Kato; Shozo Nishida
    20th IUBMB International congress of Biochemistry and molecular Biology and 11th FAOBMB Congress  2006/06
  • Nitrogen-containing bisphosphonate, YM529 inhibits RANKL expression in bone marrow stromal cell line ST2.  [Not invited]
    加藤 知里; 椿 正寛; 星野 真由美; 並松 歩美; 宇治 宏美; 柳江 正嗣; 西田 升三
    第79回日本薬理学会年会  2006/03
  • Apoptosis-inducing effect of Mevastatin on HL60 cells and its mechanism.  [Not invited]
    椿 正寛; 柳江 正嗣; 加藤 知里; 谷森 佳弘; 藤井 克樹; 西田 升三
    第79回日本薬理学会年会  2006/03
  • Enhancement of TNF-alpha induced anti-tumor activity by inhibition Protein kinase C and its mechanism  [Not invited]
    加藤 知里; 谷森 佳弘; 吉岡 昌平; 椿 正寛; 小谷 命代; 柳江 正嗣; 戸村 隆訓; 西田 升三
    第78回 日本生化学会大会  2005/10
  • A new bisphosphonate, YM529 inhibits RANKL expression in bone marrow stromal cell line ST2.  [Not invited]
    椿 正寛; 柳江 正嗣; 加藤 知里; 谷森 佳弘; 藤井 克樹; 西田 升三
    第78回 日本生化学会大会  2005/10
  • Apoptosis-inducing effect of statins on HL60 cells and its mechanism.  [Not invited]
    柳江 正嗣; 椿 正寛; 加藤 知里; 谷森 佳弘; 藤井 克樹; 西田 升三
    第78回 日本生化学会大会  2005/10
  • PKC阻害によるTNF-alpha壊死効果増強機序の解明  [Not invited]
    西田 升三; 谷森 佳弘; 椿 正寛; 柳江 正嗣; 入交 清博
    日本薬学会 第125年会  2005/03
  • DDC（diethyldithiocarbamate）によるネクローシス、アポトーシス誘導は異なるMAPKの活性化とredox調節を介して引き起こされる.  [Not invited]
    椿 正寛; 木下 さおり; 谷森 佳弘; 柳江 正嗣; 戸村 隆訓; 西田 升三
    日本薬学会 第125年会  2005/03
  • Mevastatinによる造血系腫瘍細胞株に対するアポトーシス誘導機序  [Not invited]
    柳江 正嗣; 椿 正寛; 谷森 佳弘; 入交 清博; 西田 升三
    日本薬学会 第125年会  2005/03
  • Apoptosis-inducingeffect of mevastatin on various hematopoietic tumor cell lines  [Not invited]
    椿 正寛; 谷森 佳弘; 柳江 正嗣; 戸村 隆訓; 西田 升三
    第77回 日本生化学会大会  2004/10
  • Diethyldithiocarbamate can induce two different type of cell death: apoptosis and necrosis mediating the diffential MAP kinase activation and redox regulation in HL60 cells  [Not invited]
    西田 升三; 木下 さおり; 椿 正寛; 谷森 佳弘; 柳江 正嗣; 戸村 隆訓
    第77回 日本生化学会大会  2004/10
  • C-kinase阻害によるTNFα壊死効果の増強機序  [Not invited]
    戸村 隆訓; 西田 升三; 椿 正寛; 谷森 佳弘; 柳江 正嗣; 木下 さおり; 入交 清博
    第63回 日本癌学会学術総会  2004/09
  • Mevastatinによる造血系腫瘍細胞株に対するアポトーシス誘導能  [Not invited]
    西田 升三; 椿 正寛; 谷森 佳弘; 柳江 正嗣; 戸村 隆訓
    第63回 日本癌学会学術総会  2004/09
  • 新規ビスフォスフォネート薬剤YM529の造血系腫瘍細胞株に対するアポトーシス誘導機序  [Not invited]
    西田 升三; 椿 正寛; 藤井 克樹; 谷森 佳弘; 入交 清博
    日本薬学会 第124年会  2004/03
  • Pretreatment with PKC inhibitor enhances TNF-alpha induced apoptosis in TNF-alpha resistant cells.  [Not invited]
    西田 升三; 椿 正寛; 吉岡 昌平; 藤井 克樹; 木下 さおり; 戸村 隆訓; 入交 清博
    第76回 日本生化学会大会  2003/10
  • A new bisphosphonate, YM529 induces apoptosis in HL60 cells dependent on decrease in phosphorylated ERK without Akt, p38MAPK, and NF-kappaB.  [Not invited]
    椿 正寛; 西田 升三; 藤井 克樹; 菊一 滋; 谷森 佳弘; 入交 清博
    第76回 日本生化学会大会  2003/10
  • C-kinase阻害によるTNFα壊死効果の増強とその機序の解明  [Not invited]
    西田 升三; 椿 正寛; 木下 さおり; 吉岡 昌平; 垣谷 有紀; 藤井 克樹; 戸村 隆訓; 入交 清博
    第62回 日本癌学会学術総会.  2003/09
  • 新規ビスフォスフォネート系薬剤YM529の造血系腫瘍細胞株に対するアポトーシス誘導能とその機序  [Not invited]
    入交 清博; 西田 升三; 藤井 克樹; 椿 正寛; 菊一 滋; 谷森 佳弘
    第62回 日本癌学会学術総会  2003/09
  • 新規ビスフォスフォネート系薬剤YM529による破骨細胞分化誘導抑制効果  [Not invited]
    椿 正寛; 西田 升三; 菊一 滋; 吉岡 昌平; 藤井 克樹; 小西 紀江; 入交 清博
    第52回 日本薬学会近畿支部総会  2002/10
  • 悪性黒色腫細胞におけるTNF-α耐性機構について  [Not invited]
    吉岡 昌平; 西田 升三; 小谷 命代; 椿 正寛; 藤井 克樹; 入交 清博
    第52回 日本薬学会近畿支部総会  2002/10
  • 新規ビスフォスフォネート系薬剤YM529によるアポトーシス誘導機序の検討  [Not invited]
    藤井 克樹; 西田 升三; 菊一 滋; 吉岡 昌平; 椿 正寛; 入交 清博
    第52回 日本薬学会近畿支部総会  2002/10

MISC

  • 多発性骨髄腫分泌HGFによる骨髄間質細胞および骨芽細胞でのRANKL発現促進機構の解析
    田畑 光希; 椿 正寛; 武田 朋也; 関 しおり; 西田 升三  日本薬学会年会要旨集  140年会-  27Q  -pm128  2020/03
  • Rho/YAP経路活性化を介したRHAMM及びCXCR4過剰発現は転移を促進する(Overexpression of RHAMM and CXCR4 via activation of Rho/YAP pathway promotes tumor metastasis)
    源野 秀次; 椿 正寛; 武田 朋也; 田畑 光希; 西田 升三  日本癌学会総会記事  78回-  P  -2052  2019/09
  • 骨髄腫分泌HGFは骨芽細胞におけるRANKL発現増加を介して骨破壊を促進する(Myeloma cellssecreted HGF accelerate the bone destruction via increased RANKL expression in osteoblasts)
    田畑 光希; 椿 正寛; 武田 朋也; 関 しおり; 西田 升三  日本癌学会総会記事  78回-  P  -2088  2019/09
  • MEK阻害薬は抗がん剤誘発末梢神経障害を抑制できる(MEK inhibitor suppressed the anticancer drug-induced neuropathy)
    加藤 菜月; 椿 正寛; 武田 朋也; 立石 敬典; 西田 升三  日本癌学会総会記事  78回-  P  -3143  2019/09
  • シンバスタチンによるオキサリプラチン誘発末梢神経障害抑制及び抗腫瘍作用増強効果(Simvastatin inhibited the oxaliplatin-induced neuropathy and potentiate antitumor effect of oxaliplatin)
    立石 敬典; 椿 正寛; 武田 朋也; 加藤 菜月; 西田 升三  日本癌学会総会記事  78回-  P  -3176  2019/09
  • ベムラフェニブによるBRAF変異大腸癌でのオキサリプラチン及び5-FU殺細胞作用増強効果(Vemurafenib enhances sensitivity of oxaliplatin and 5-fluorourasil in BRAF-mutated colorectal cancer)
    地主 みなみ; 椿 正寛; 武田 朋也; 関 しおり; 西田 升三  日本癌学会総会記事  78回-  P  -3154  2019/09
  • 大腸がんにおけるPI3K/Akt経路活性化を介したMEK阻害薬耐性機構(Activation of PI3K/Akt pathway contributes MEK inhibitor resistance in colon cancer)
    椿 正寛; 武田 朋也; 加藤 菜月; 立石 敬典; 西田 升三  日本癌学会総会記事  78回-  P  -3156  2019/09
  • シグナル活性化を介したHIF-1過剰発現が骨髄腫でのメルファラン耐性に関与する(Overexpression of HIF-1alpha by activation of signal pathway involved with melphalan resistance in myeloma)
    松田 拓弥; 椿 正寛; 武田 朋也; 田畑 光希; 関 しおり; 西田 升三  日本癌学会総会記事  78回-  P  -3163  2019/09
  • ダカルバジン及びスタチン併用療法は転移における生存率を改善できる(Combination treatment with dacarbazine and statins improved survival rate in melanoma metastasis-bearing mice)
    西田 升三; 椿 正寛; 武田 朋也; 地主 みなみ; 関 しおり  日本癌学会総会記事  78回-  P  -3338  2019/09
  • ソラフェニブによる悪性黒色腫での受容体型チロシンキナーゼ抑制を介した腫瘍増殖・転移抑制効果(Sorafenib suppresses the tumor growth and metastasis of melanoma through suppression of receptor tyrosine kinase pathway)
    武田 朋也; 椿 正寛; 地主 みなみ; 源野 秀次; 西田 升三  日本癌学会総会記事  78回-  P  -3339  2019/09
  • ERK1/2, Akt, NF-κB活性化を介したBim発現低下が骨髄腫での多剤耐性に中心的役割を果たす(Decreasing Bim expression via activated ERK, Akt, and NF-kappaB play a central role in multidrugresistant myeloma cells)
    関 しおり; 椿 正寛; 武田 朋也; 地主 みなみ; 西田 升三  日本癌学会総会記事  78回-  P  -3358  2019/09
  • Dimethyl fumarateによるNF-kappaB抑制を介した腫瘍増殖及び転移抑制効果(Dimethyl fumarate suppresses the tumor growth and metastasis through suppression of NF-kappaB)
    武田 朋也; 椿 正寛; 浅野 良太; 川島 啓司; 田畑 光希; 西田 升三  日本癌学会総会記事  77回-  389  -389  2018/09
  • レバミピドによる口腔粘膜細胞でのAkt/mTOR経路活性化を介した抗がん剤誘導細胞死抑制効果(Rebamipide suppressed anticancer drugs-induced cell death via Akt/mTOR activation in oral mucosal keratinocytes)
    川島 啓司; 椿 正寛; 武田 朋也; 浅野 良太; 藤本 伸一郎; 西田 升三  日本癌学会総会記事  77回-  694  -694  2018/09
  • シグナル伝達因子活性化によるBim発現低下を介したアドリアマイシン耐性獲得機序(Downregulation of Bim via activation of signal molecules plays a central role in adriamycin resistant-myeloma cells)
    河本 雄一; 椿 正寛; 武田 朋也; 浅野 良太; 西田 升三  日本癌学会総会記事  77回-  834  -834  2018/09
  • PKC阻害剤による抗がん剤誘発末梢神経障害抑制効果(PKC inhibitor suppressed the anticancer drug-induced neuropathy)
    加藤 菜月; 椿 正寛; 武田 朋也; 河本 雄一; 川島 啓司; 西田 升三  日本癌学会総会記事  77回-  854  -854  2018/09
  • スタチンによる造血器腫瘍でのRas経路阻害を介したアポトーシス誘導効果(Statins induce apoptosis via inhibition of Ras/ERK and Ras/mTOR signaling pathways in hematopoietic tumor)
    西田 升三; 椿 正寛; 武田 朋也; 藤原 大一朗; 河本 雄一; 藤本 伸一郎  日本癌学会総会記事  77回-  1460  -1460  2018/09
  • Statins及びダカルバジン併用投与による腫瘍増殖及び転移抑制効果(Combined treatment of statins and dacarbazine inhibit tumor growth and metastasis in melanoma)
    椿 正寛; 武田 朋也; 川島 啓司; 地主 みなみ; 西田 升三  日本癌学会総会記事  77回-  1605  -1605  2018/09
  • 新規NF-kappaB/STAT3阻害剤による多発性骨髄腫でのアポトーシス誘導効果(A novel NF-kappaB/STAT3 inhibitor, bavachin, induces apoptosis in multiple myeloma cell lines)
    浅野 良太; 椿 正寛; 武田 朋也; 加藤 菜月; 田畑 光希; 西田 升三  日本癌学会総会記事  77回-  1709  -1709  2018/09
  • HGFは骨髄間質細胞及び骨芽細胞におけるRANKL発現を増加させる(HGF accelerate RANKL expression in bone marrow stromal cells and osteoblasts)
    田畑 光希; 椿 正寛; 武田 朋也; 加藤 菜月; 西田 升三  日本癌学会総会記事  77回-  2151  -2151  2018/09
  • レバミピドは口腔粘膜細胞においてAkt経路活性化により5-fluorourasil誘導細胞死を抑制する
    川島 啓司; 椿 正寛; 武田 朋也; 浅野 良太; 藤本 伸一郎; 西田 升三  日本薬学会年会要旨集  138年会-  (4)  67  -67  2018/03
  • 多発性骨髄腫でのMIP-1αオートクラインはERK及びAkt経路活性化により抗がん剤耐性に寄与する
    河本 雄一; 椿 正寛; 武田 朋也; 川島 啓司; 西田 升三  日本薬学会年会要旨集  138年会-  (4)  68  -68  2018/03
  • 慢性骨髄性白血病におけるBCR-ABL1阻害薬耐性にMET経路活性化が寄与する
    椿 正寛; 武田 朋也; 河本 雄一; 浅野 良太; 藤本 伸一郎; 山添 譲; 西田 升三  日本薬学会年会要旨集  138年会-  (4)  68  -68  2018/03
  • PioglitazoneはPPARγ非依存的にSTAT3阻害を介してアポトーシスを誘導する
    浅野 良太; 椿 正寛; 武田 朋也; 川島 啓司; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  138年会-  (4)  68  -68  2018/03
  • Dimethyl fumarateによる悪性黒色腫でのNF-κB阻害を介した腫瘍増殖・転移抑制効果
    武田 朋也; 椿 正寛; 浅野 良太; 川島 啓司; 西田 升三  日本薬学会年会要旨集  138年会-  (4)  69  -69  2018/03
  • StatinsによるRas経路阻害を介したBim発現増加でのアポトーシス誘導機序
    西田 升三; 椿 正寛; 武田 朋也; 眞下 恵次; 藤本 伸一郎; 阪口 勝彦  日本薬学会年会要旨集  138年会-  (4)  193  -193  2018/03
  • 新規NF-kappaB/STAT3阻害剤による多発性骨髄腫でのアポトーシス誘導機構の解析
    小泉 翔太郎; 椿 正寛; 武田 朋也; 浅野 良太; 川島 啓司; 西田 升三  日本薬学会年会要旨集  138年会-  (4)  195  -195  2018/03
  • 多発性骨髄腫でのRANK/RANKLを介した抗がん剤耐性はSrc経路活性化が関与する
    宇佐見 拓丈; 椿 正寛; 武田 朋也; 河本 雄一; 西田 升三  日本薬学会年会要旨集  138年会-  (4)  198  -198  2018/03
  • 多発性骨髄腫でのメルファラン耐性にシグナル伝達経路活性化によるHIF-1alpha過剰発現が関与する
    友成 佳加; 椿 正寛; 武田 朋也; 藤本 伸一郎; 西田 升三  日本癌学会総会記事  76回-  P  -1367  2017/09
  • Src阻害はRANK/RANKLによるCAM-DRを克服する
    西田 升三; 椿 正寛; 武田 朋也; 友成 佳加; 川島 啓司  日本癌学会総会記事  76回-  P  -1369  2017/09
  • Rebamipideは口腔癌において5-fluorourasil感受性を増強させる
    川島 啓司; 椿 正寛; 武田 朋也; 河本 雄一; 西田 升三  日本癌学会総会記事  76回-  P  -1378  2017/09
  • CMLにおけるイマチニブ耐性にMET/ERK及びMET/JNK経路が関与する
    椿 正寛; 武田 朋也; 河本 雄一; 藤本 伸一郎; 西田 升三  日本癌学会総会記事  76回-  E  -2036  2017/09
  • 新規NIK阻害剤Mangiferinによる転移・腫瘍増殖抑制効果
    武田 朋也; 椿 正寛; 浅野 良太; 川島 啓司; 西田 升三  日本癌学会総会記事  76回-  J  -2107  2017/09
  • PioglitazoneはSTAT3阻害を介してSurvivinの発現低下及びAIFの発現増加によりアポトーシスを誘導する
    浅野 良太; 椿 正寛; 武田 朋也; 河本 雄一; 西田 升三  日本癌学会総会記事  76回-  P  -2347  2017/09
  • MIP-1alphaオートクラインは多発性骨髄腫でのメルファラン感受性を低下させる
    河本 雄一; 椿 正寛; 武田 朋也; 友成 佳加; 眞下 恵次; 阪口 勝彦; 西田 升三  日本癌学会総会記事  76回-  J  -3113  2017/09
  • 多発性骨髄腫でのメルファラン耐性にはHIF-1αの過剰発現が寄与する
    友成 佳加; 椿 正寛; 武田 朋也; 眞下 恵次; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  137年会-  (4)  83  -83  2017/03
  • RANK/RANKLを介した多発性骨髄腫での抗がん剤耐性獲得機序
    椿 正寛; 武田 朋也; 友成 佳加; 眞下 恵次; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  137年会-  (4)  83  -83  2017/03
  • 多発性骨髄腫でのNF-κB阻害薬mangiferinと抗がん剤併用による細胞死誘導増強効果
    西田 升三; 河本 雄一; 椿 正寛; 武田 朋也; 友成 佳加; 藤本 伸一郎; 山添 譲  日本薬学会年会要旨集  137年会-  (4)  84  -84  2017/03
  • 新規NIK阻害剤mangiferin投与による腫瘍増殖・転移抑制効果
    武田 朋也; 椿 正寛; 友成 佳加; 藤本 伸一郎; 山添 譲; 西田 升三  日本薬学会年会要旨集  137年会-  (4)  84  -84  2017/03
  • 西田 升三; 椿 正寛  薬学雑誌  137-  (2)  145  -149  2017/02
  • 藤原 大一朗; 眞下 惠次; 木村 佳世; 野田 明宏; 多喜 和夫; 芳林 浩史; 武田 朋也; 椿 正寛; 西田 升三; 阪口 勝彦  癌と化学療法  44-  (2)  149  -152  2017/02
  • 新規NIK阻害薬によるNF-kappaB経路抑制を介したアポトーシス誘導機序
    武田 朋也; 椿 正寛; 木野 稔己; 友成 佳加; 眞下 恵次; 阪口 勝彦; 西田 升三  日本癌学会総会記事  75回-  J  -2032  2016/10
  • 慢性骨髄性白血病におけるMET活性化はイマチニブ耐性に寄与する
    椿 正寛; 武田 朋也; 木野 稔己; 友成 佳加; 藤本 伸一郎; 西田 升三  日本癌学会総会記事  75回-  J  -2035  2016/10
  • HIF-1alphaの過剰発現は多発性骨髄腫でのメルファラン耐性に寄与する
    西田 升三; 椿 正寛; 武田 朋也; 木野 稔己; 友成 佳加; 藤本 伸一郎  日本癌学会総会記事  75回-  J  -3021  2016/10
  • RANK/RANKLによる細胞接着を介した抗がん剤耐性機構の解析
    木野 稔己; 椿 正寛; 武田 朋也; 友成 佳加; 眞下 恵次; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本癌学会総会記事  75回-  P  -3262  2016/10
  • Mangiferinは多発性骨髄腫において抗がん剤感受性を増強させる
    友成 佳加; 椿 正寛; 武田 朋也; 木野 稔己; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本癌学会総会記事  75回-  P  -3285  2016/10
  • PKC及びMEK阻害剤によるオキサリプラチン誘発末梢神経障害の抑制及び抗腫瘍効果の増強
    椿 正寛; 武田 朋也; 木野 稔己; 藤原 大一朗; 山添 譲; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  136年会-  (4)  72  -72  2016/03
  • Survivinは多発性骨髄腫のvincristine耐性獲得に寄与する
    木野 稔己; 椿 正寛; 武田 朋也; 眞下 恵次; 山添 譲; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  136年会-  (4)  75  -75  2016/03
  • NIK阻害剤による多発性骨髄腫の細胞死誘導効果及びその作用機序の解明
    武田 朋也; 椿 正寛; 木野 稔己; 眞下 恵次; 山添 譲; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  136年会-  (4)  75  -75  2016/03
  • PKN3ノックアウトマウスを用いた新たな血管新生とがん転移シグナルの制御機構
    窪内 康二; 辻本 翔; 神田 勇輝; 小野 祐輝; 木戸 友絵; 澤田 奈々; 西田 升三; 椿 正寛; Rana Mashud; 向井 秀幸; 杉浦 麗子  日本生化学会大会・日本分子生物学会年会合同大会講演要旨集  88回・38回-  [2P1146]  -[2P1146]  2015/12
  • 尾垣 光彦; 相馬 沙希; 佐々木 恭子; 近藤 裕志; 森垣 和馬; 田中 聡之; 椿 正寛; 西田 升三; 高垣 佳史; 畑中 智子  日本医療薬学会年会講演要旨集  25-  434  -434  2015/10
  • Dimethyl fumarateによるNF-kappaB阻害を介したアポトーシス誘導効果
    木野 稔己; 椿 正寛; 武田 朋也; 小川 直希; 石坂 敏彦; 西田 升三  日本癌学会総会記事  74回-  P  -1189  2015/10
  • PKC阻害剤はオキサリプラチン誘導末梢神経障害を抑制するとともに抗腫瘍効果を増強させる
    椿 正寛; 武田 朋也; 中橋 拓也; 小川 直希; 石坂 敏彦; 西田 升三  日本癌学会総会記事  74回-  J  -1192  2015/10
  • Bisphosphonates及びstatinsによる骨髄腫でのRas経路阻害を介したMIP-1alpha発現抑制効果
    武田 朋也; 椿 正寛; 木野 稔己; 眞下 恵次; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本癌学会総会記事  74回-  J  -1209  2015/10
  • Survivinの発現増加が多発性骨髄腫におけるvincristine耐性に中心的な役割を果たす
    西田 升三; 椿 正寛; 武田 朋也; 眞下 恵次; 藤原 大一朗; 阪口 勝彦  日本癌学会総会記事  74回-  P  -2314  2015/10
  • Nitrogen-containing bisphosphonatesによるRas経路阻害を介したBim発現増加によるアポトーシス誘導機序
    嶌岡 弘高; 椿 正寛; 武田 朋也; 坂本 洸太郎; 藤田 亜里沙; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 石坂 敏彦; 西田 升三  日本薬学会年会要旨集  135年会-  (4)  60  -60  2015/03
  • Statins投与でのRho阻害による腫瘍増殖・転移抑制効果
    坂下 洸太郎; 椿 正寛; 武田 朋也; 嶌岡 弘高; 藤田 亜里沙; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 石坂 敏彦; 西田 升三  日本薬学会年会要旨集  135年会-  (4)  61  -61  2015/03
  • RANK/RANKLによるNF-κB活性化を介したEMT誘導に基づく浸潤促進効果
    武田 朋也; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 藤田 亜里沙; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 石坂 敏彦; 西田 升三  日本薬学会年会要旨集  135年会-  (4)  61  -61  2015/03
  • Bisphosphonates及びstatinsによる多発性骨髄腫でのMIP-1α分泌抑制効果
    椿 正寛; 武田 朋也; 嶌岡 弘高; 坂本 洸太郎; 藤田 亜里沙; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 石坂 敏彦; 西田 升三  日本薬学会年会要旨集  135年会-  (4)  206  -206  2015/03
  • RANKL/RANKシステムによる乳がんでのNF-kappaB活性化を介したEMT促進効果(Activation of NF-kappaB by the RANKL/RANK system induces EMT in mammary tumor cell lines)
    武田 朋也; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 藤田 亜梨沙; 小川 直希; 山添 譲; 向井 淳治; 西田 升三  日本癌学会総会記事  73回-  J  -2076  2014/09
  • StatinsによるRho経路阻害を介した腫瘍増殖・転移抑制効果(Statins inhibit tumor growth and metastasis through the suppression of Rho signaling pathway)
    坂本 洸太郎; 椿 正寛; 武田 朋也; 嶌岡 弘高; 藤田 亜梨沙; 眞下 恵次; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本癌学会総会記事  73回-  J  -3050  2014/09
  • RANK/RANKLシステムによるシグナル伝達経路活性化を介した多剤耐性獲得機序(Induction of multidrug resistance in multiple myeloma by RANK/RANKL system mediates activation of signaling pathway)
    椿 正寛; 武田 朋也; 坂本 洸太郎; 嶌岡 弘高; 藤田 亜梨沙; 眞下 恵次; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本癌学会総会記事  73回-  J  -1112  2014/09
  • Src阻害に基づく抗がん剤耐性多発性骨髄腫での耐性克服効果(By inhibiting Src overcome multidrug resistance in multidrug-resistant myeloma cells)
    藤田 亜梨沙; 椿 正寛; 武田 朋也; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 山添 譲; 向井 淳治; 西田 升三  日本癌学会総会記事  73回-  J  -1114  2014/09
  • ビスフォスフォネート及びスタチンによるMIP-1alpha分泌抑制効果(Bisphosphonates and statin inhibits MIP-1alpha secretion in myeloma cells)
    西田 升三; 椿 正寛; 武田 朋也; 嶌岡 弘高; 坂本 洸太郎; 藤田 亜梨沙; 小川 直希; 山添 譲; 向井 淳治  日本癌学会総会記事  73回-  P  -2239  2014/09
  • 大腸癌でのRas経路阻害による抗がん剤感受性増強効果(Inhibition of Ras pathway enhances the cytotoxic effects of anti-cancer drug in colon cancer)
    嶌岡 弘高; 椿 正寛; 武田 朋也; 坂本 洸太郎; 藤田 亜梨沙; 眞下 恵次; 藤原 大一朗; 阪口 勝彦; 西田 升三  日本癌学会総会記事  73回-  P  -1387  2014/09
  • 眞下 惠次; 藤原 大一朗; 木村 佳世; 野田 明宏; 武田 朋也; 椿 正寛; 西田 升三; 阪口 勝彦  日本医療薬学会年会講演要旨集  24-  284  -284  2014/08
  • 藤原 大一朗; 眞下 惠次; 木村 佳世; 野田 明宏; 武田 朋也; 椿 正寛; 西田 升三; 阪口 勝彦  日本医療薬学会年会講演要旨集  24-  391  -391  2014/08
  • 多発性骨髄腫でのTNF-αオートクライン阻害によるmTOR及びNF-κB抑制を介した抗がん剤感受性増強効果
    椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  134年会-  (4)  189  -189  2014/03
  • Statinsによる悪性黒色腫でのRho経路阻害を介した転移抑制・延命効果
    坂本 洸太郎; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  134年会-  (4)  191  -191  2014/03
  • Nitrogen-containing bisphosphonatesによるRas/ERK及びRas/mTOR経路阻害を介したアポトーシス誘導機序
    嶌岡 弘高; 椿 正寛; 駒居 真紀子; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  134年会-  (4)  191  -191  2014/03
  • 多発性骨髄腫での抗がん剤耐性獲得機序 シグナル伝達因子活性化によるMDR1、Survivin及びBimの発現調節
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 向井 淳治; 阪口 勝彦; 西田 升三  日本薬学会年会要旨集  134年会-  (4)  191  -191  2014/03
  • BisphosphonatesによるRas阻害を介した造血器腫瘍でのアポトーシス誘導機序(Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras pathways)
    嶌岡 弘高; 椿 正寛; 駒居 真紀子; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三  日本癌学会総会記事  72回-  191  -191  2013/10
  • RANK/RANKLを介した抗がん剤耐性獲得機序(Multi-drug resistance in multiple myeloma mediates RANK/RANKL system)
    椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三  日本癌学会総会記事  72回-  192  -192  2013/10
  • シグナル伝達因子活性化による多発性骨髄腫での抗がん剤耐性獲得機序(Multidrug-resistance in multiple myeloma mediates activation of signal transduction molecules)
    駒居 真紀子; 椿 正寛; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三  日本癌学会総会記事  72回-  467  -467  2013/10
  • TNF-alphaオートクライン阻害による抗がん剤殺細胞作用増強効果(Inhibition of the tumor necrosis factor-alpha autocrine enhances the sensitivity of myeloma cells to anticancer drugs)
    西田 升三; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 坂本 洸太郎; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 向井 淳治  日本癌学会総会記事  72回-  470  -470  2013/10
  • StatinsによるRho/LINK経路阻害を介した転移抑制効果(Statins inhibit metastasis through the suppression of Rho/LIMK pathway)
    坂本 洸太郎; 椿 正寛; 駒居 真紀子; 嶌岡 弘高; 小川 直希; 眞下 恵次; 藤原 大一朗; 山添 譲; 阪口 勝彦; 向井 淳治; 西田 升三  日本癌学会総会記事  72回-  495  -495  2013/10
  • 伊藤武志; 川口範明; 古川諭; 柳江正嗣; 野村守弘; 椿正寛; 西田升三; 山添譲  日本緩和医療学会学術大会プログラム・抄録集  18回-  441  -441  2013/06
  • 椿正寛; 駒居真紀子; 小川直希; 山添譲; 向井淳治; 西田升三  日本薬学会年会要旨集(CD-ROM)  133年会-  (3)  208  -208  2013/03
  • 嶌岡弘高; 椿正寛; 駒居真紀子; 小川直希; 山添譲; 向井淳治; 西田升三  日本薬学会年会要旨集(CD-ROM)  133年会-  (4)  131  -131  2013/03
  • 駒居真紀子; 椿正寛; 小川直希; 山添譲; 向井淳治; 西田升三  日本薬学会年会要旨集(CD-ROM)  133年会-  (4)  61  -61  2013/03
  • 伊藤武志; 川口範明; 古川諭; 柳江正嗣; 野村守弘; 椿正寛; 西田升三; 山添譲  日本在宅医療学会学術集会プログラム・抄録集  24th-  107  2013
  • 柳江正嗣; 椿正寛; 中尾真理子; 藤原季美子; 浅野肇; 森田哲也; 野村守弘; 山添譲; 西田升三  日本医療薬学会年会講演要旨集  22nd-  325  2012/10
  • 柳江 正嗣; 椿 正寛; 中尾 真理子; 藤原 季美子; 浅野 肇; 森田 哲也; 野村 守弘; 山添 譲; 西田 升三  日本医療薬学会年会講演要旨集  22-  325  -325  2012/10
  • 多発性骨髄腫でのMDR1、survivinの過剰発現及びBimの発現低下を介した抗がん剤耐性獲得(Overexpression of MDR1 and survivin, and decreased Bim expression mediate multidrug-resistance in multiple myeloma)
    駒居 真紀子; 椿 正寛; 小川 直希; 山添 譲; 向井 淳治; 西田 升三  日本癌学会総会記事  71回-  326  -326  2012/08
  • ミノドロネートによる骨肉腫細胞での転移抑制効果(Reduction of metastasis in osteosarcoma by minodronic acid)
    西田 升三; 椿 正寛; 駒井 真紀子; 小川 直希; 山添 譲; 向井 淳治  日本癌学会総会記事  71回-  504  -504  2012/08
  • Pioglitazoneによる抗がん剤殺細胞増強効果(Pioglitazone enhances the cytotoxic effects of anti-cancer drugs in head and neck carcinoma)
    椿 正寛; 駒居 真紀子; 小川 直希; 山添 譲; 向井 淳治; 西田 升三  日本癌学会総会記事  71回-  569  -569  2012/08
  • Masashi Yanae; Mariko Nakao; Kimiko Fujiwara; Akinori Kawaguchi; Masanobu Tsubaki; Yasutaka Chiba; Tetsuya Morita; Yuzuru Yamazoe; Shozo Nishida  Japanese Journal of Cancer and Chemotherapy  39-  (7)  1093  -1098  2012/07
  • 椿正寛; 柳江正嗣; 山添譲; 松岡寛; 西田升三  日本薬学会年会要旨集  132年会-  (4)  238  -238  2012/03
  • 柳江正嗣; 中尾真理子; 藤原季美子; 椿正寛; 廣瀬雄司; 森田哲也; 山添譲; 西田升三  日本医療薬学会年会講演要旨集  21st-  238  -238  2011/09
  • 木寺 康裕; 中尾 將彦; 椿 正寛; 吉長 正紘; 中尾 真理子; 渡辺 瑞貴; 森本 陽之; 坂野 実加; 浅野 肇; 柳江 正嗣; 藤原 季美子; 竹内 昌司; 千葉 康敬; 山添 譲; 西田 升三  日本医療薬学会年会講演要旨集  21-  158  -158  2011/09
  • 柳江 正嗣; 中尾 真理子; 藤原 季美子; 椿 正寛; 廣瀬 雄司; 森田 哲也; 山添 譲; 西田 升三  日本医療薬学会年会講演要旨集  21-  238  -238  2011/09
  • YM529/ONO-5920による悪性黒色腫細胞での肺転移抑制効果(Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits tumor metastasis in mouse melanoma)
    西田 升三; 椿 正寛; 柳江 正嗣; 木寺 康裕; 尾垣 光彦  日本癌学会総会記事  70回-  121  -121  2011/09
  • Statinによる血管新生促進因子発現阻害効果(Blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathways by statins reduces angiogenic factors in mouse osteosarcoma)
    椿 正寛; 柳江 正嗣; 木寺 康裕; 尾垣 光彦; 西田 升三  日本癌学会総会記事  70回-  125  -125  2011/09
  • 木寺 康裕; 中尾 將彦; 椿 正寛; 吉長 正紘; 梶谷 文裕; 柳江 正嗣; 坂野 実加; 山添 譲; 千葉 康敬; 森山 健三; 西田 升三  癌と化学療法  38-  (7)  1143  -1148  2011/07
  • YM529/ONO-5920によるマウス悪性黒色腫での浸潤、運動、接着、及び転移抑制効果
    椿 正寛; 金子 淳一; 木寺 康裕; 柳江 正嗣; 岡本 龍治; 山添 譲; 西田 升三  日本薬学会年会要旨集  131年会-  (4)  326  -326  2011/03
  • DimethylfumarateによるNF-kappaB阻害を介した細胞浸潤および転移抑制効果
    岡本 龍治; 椿 正寛; 金子 淳一; 山添 譲; 松岡 寛; 木寺 康裕; 柳江 正嗣; 西田 升三  日本薬学会年会要旨集  131年会-  (4)  326  -326  2011/03
  • 木寺康裕; 佐藤太郎; 藤原季美子; 山添譲; 森山健三; 文田壮一; 上田眞也; 岡本渉; 岡本邦夫; 鶴谷純司; 宮崎昌樹; 岡本勇; 椿正寛; 西田升三; 中川和彦  日本消化管学会総会学術集会プログラム・抄録集  7th-  334  2011
  • NF-κB阻害剤はマトリックスメタロプロテイナーゼの発現および活性を阻害することにより腫瘍細胞浸潤および転移を抑制する(NF-kappaB inhibitor suppresses tumor cell invasion and metastasis by inhibiting the expression and activities of matrix metalloproteinases)
    金子 淳一; 椿 正寛; 山添 譲; 谷森 佳弘; 木寺 康裕; 柳江 正嗣; 西田 升三  日本生化学会大会・日本分子生物学会年会合同大会講演要旨集  83回・33回-  4P  -0992  2010/12
  • タモキシフェンによるMMPs発現及び浸潤阻害を介した転移抑制効果(Tamoxifen inhibits tumor metastasis through suppression of invasion and MMPs expression in mouse melanoma)
    西田 升三; 金子 淳一; 椿 正寛; 松岡 寛; 木寺 康裕; 柳江 正嗣; 谷森 佳弘; 藤原 季美子; 森山 健三  日本癌学会総会記事  69回-  188  -189  2010/08
  • DMFによるNF-kappaB抑制を介した転移抑制効果(Dimethylfumarate inhibit lung metastasis through the suppression of NF-kappaB signaling)
    椿 正寛; 山添 譲; 松岡 寛; 金子 淳一; 木寺 康裕; 柳江 正嗣; 谷森 佳弘; 藤原 季美子; 森山 健三; 西田 升三  日本癌学会総会記事  69回-  420  -420  2010/08
  • マンギフェリンによる急性骨髄性白血病細胞におけるアポトーシス誘導機序の解明
    椿 正寛; 礒野 藍; 礒崎 美沙子; 佐藤 健太郎; 金子 淳一; 荘子 夏緒里; 尾垣 光彦; 山添 譲; 木寺 康裕; 谷森 佳弘; 柳江 正嗣; 森山 健三; 松田 秀秋; 西田 升三  日本薬学会年会要旨集  130年会-  (3)  75  -75  2010/03
  • 木寺康裕; 佐藤太郎; 藤原季美子; 山添譲; 森山健三; 文田壮一; 上田眞也; 岡本渉; 岡本邦夫; 鶴谷純司; 宮崎昌樹; 岡本勇; 椿正寛; 西田升三; 中川和彦  日本臨床腫瘍学会学術集会プログラム・抄録集  8th-  256  2010
  • 木寺 康裕; 月岡 康行; 山添 譲; 森山 健三; 椿 正寛; 西田 升三  日本医療薬学会年会講演要旨集  19-  302  -302  2009/09
  • MIP-1 alphaはMEK/ERK経路を介して破骨細胞分化を誘導する(Macrophage inflammatory protein-1 alpha induces osteoclast formation by activation of MEK/ERK pathway)
    西田 升三; 椿 正寛; 礒崎 美沙子; 礒野 藍; 佐藤 健太郎; 金子 淳一; 山添 譲; 木寺 康弘; 谷森 佳弘  日本癌学会総会記事  68回-  444  -444  2009/08
  • タモキシフェンはPKC阻害を介して転移を抑制する(Tamoxifen inhibits tumor metastasis through the suppression of PKC in mouse melanoma)
    椿 正寛; 松岡 寛; 礒崎 美沙子; 礒野 藍; 佐藤 健太郎; 金子 淳一; 荘子 夏緒里; 尾垣 光彦; 中村 春行; 柳江 正嗣; 西田 升三  日本癌学会総会記事  68回-  485  -485  2009/08
  • PKC阻害薬による接着阻害を介した転移抑制効果
    椿 正寛; 松岡 寛; 礒崎 美沙子; 礒野 藍; 佐藤 健太郎; 山添 譲; 藤原 季美子; 谷森 佳弘; 木寺 康弘; 森山 健三; 中村 春行; 尾垣 光彦; 西田 升三  日本薬学会年会要旨集  129年会-  (4)  312  -312  2009/03
  • StatinはRas/MEK/ERK経路を抑制することでがん細胞に対してアポトーシスを誘導する(Statin induces apoptosis in various tumor cells dependently on inhibition by Ras/MEK/ERK pathway)
    椿 正寛; 西之坊 実里; 礒野 藍; 礒崎 美沙子; 佐藤 健太郎; 山添 譲; 谷森 佳弘; 木寺 康裕; 森山 健三; 西田 升三  日本癌学会総会記事  67回-  131  -131  2008/09
  • MIP-1alphaによる骨髄間質細胞および骨芽細胞でのRANKL発現促進効果(MIP-1 alpha increases a RANKL expression in bone marrow stromal cells and osteoblasts through MAPK and PI3K/Akt pathway)
    礒野 藍; 椿 正寛; 西之坊 実里; 礒崎 美沙子; 佐藤 健太郎; 山添 譲; 木寺 康裕; 谷森 佳弘; 森山 健三; 西田 升三  日本癌学会総会記事  67回-  149  -149  2008/09
  • PKC阻害剤は悪性黒色腫における腫瘍浸潤を抑制する(PKC inhibitor suppresses tumor cell invasion in mouse melanoma cells)
    礒崎 美沙子; 椿 正寛; 西之坊 実里; 礒野 藍; 佐藤 健太郎; 荘子 夏緒里; 尾垣 光彦; 中村 春行; 松岡 寛; 西田 升三  日本癌学会総会記事  67回-  186  -186  2008/09
  • 窒素含有ビスホスホネート、YM529/ONO5920による骨髄腫でのMIP-1alpha分泌抑制(Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits MIP-1 alpha secretion in myeloma cells)
    西之坊 実里; 椿 正寛; 礒野 藍; 礒崎 美沙子; 佐藤 健太郎; 山添 譲; 谷森 佳弘; 木寺 康裕; 森山 健三; 西田 升三  日本癌学会総会記事  67回-  308  -309  2008/09
  • PKC阻害剤はタイプIおよびタイプIVコラーゲンとの接着を阻害することで転移を抑制する(Protein kinase C inhibitor inhibited metastasis through suppression of cell adhesion to type I and type IV collagen)
    佐藤 健太郎; 椿 正寛; 西之坊 実里; 礒野 藍; 礒崎 美沙子; 荘子 夏緒里; 尾垣 光彦; 中村 春行; 松岡 寛; 西田 升三  日本癌学会総会記事  67回-  367  -367  2008/09
  • MIP-1αによるRANKL発現促進効果およびその機序の解明
    椿 正寛; 西之坊 実里; 尾垣 光彦; 山添 譲; 松岡 寛; 荘子 夏緒里; 中村 春行; 西田 升三  日本薬学会年会要旨集  128年会-  (4)  109  -109  2008/03
  • Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Saori Nishiura; Takeru Kawaguchi; Mitsuhiko Ogaki; Minori Nishinobo; Kenji Shimamoto; Kenzo Moriyama; Shozo Nishida  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN  128-  (1)  153  -158  2008/01
  • マウス骨髄間質細胞及び骨芽細胞においてマクロファージ炎症性蛋白質1α(MIP-1α)は核因子κBリガンドの受容体活性化因子(RANKL)の発現を増強する(Macrophage inflammatory protein-1alpha (MIP-1alpha) enhances a receptor activator of nuclear factor kappaB ligand (RANKL) expression in mouse bone marrow stromal cells and osteoblast)
    西之坊 実里; 椿 正寛; 尾垣 光彦; 山添 譲; 藤原 季美子; 松岡 寛; 西浦 早織; 西田 升三  日本生化学会大会・日本分子生物学会年会合同大会講演要旨集  80回・30回-  4T18  -3  2007/11
  • タンパク質キナーゼC阻害剤H7は細胞接着阻害を介してマウス黒色腫の肺転移を抑制する(Protein kinase C inhibitor, H7, inhibits lung metastasis in mouse melanoma through suppression of cell adhesion)
    椿 正寛; 尾垣 光彦; 西之坊 実里; 藤原 季美子; 山添 譲; 森山 健三; 西田 升三  日本癌学会総会記事  66回-  147  -147  2007/08
  • PKC阻害剤H7はERK1/2活性化の抑制を介して腫瘍浸潤を抑制する(The PKC inhibitor, H7, inhibits tumor cell invasion and through the suppression of ERK1/2 activation)
    尾垣 光彦; 椿 正寛; 西之坊 実里; 藤原 季美子; 山添 譲; 森山 健三; 西田 升三  日本癌学会総会記事  66回-  147  -148  2007/08
  • HL60細胞においてメバスタチンはリン酸化ERK1/2減少依存性にアポトーシスを誘導する(Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK1/2)
    西之坊 実里; 椿 正寛; 尾垣 光彦; 藤原 季美子; 山添 譲; 森山 健三; 西田 升三  日本癌学会総会記事  66回-  366  -366  2007/08
  • 新規ビスホスホネートYM529はリン酸化ERK1/2減少依存性にHL60細胞のアポトーシスを誘導する(A novel bisphosphonate, YM529, induces apoptosis in HL60 cells dependent on decrease in phosphorylated ERK1/2)
    藤原 季美子; 椿 正寛; 尾垣 光彦; 西之坊 実里; 山添 譲; 森山 健三; 西田 升三  日本癌学会総会記事  66回-  366  -366  2007/08
  • 椿本 貴教; 高坂 一貴; 齋藤 正寛; 寺中 敏夫  日本歯科保存学雑誌  50-  (3)  292  -301  2007/06
  • PKC阻害薬によるMMPs分泌阻害でのがん細胞浸潤抑制効果
    椿 正寛; 尾垣 光彦; 加藤 知里; 谷森 佳弘; 柳江 正嗣; 西田 升三  日本薬学会年会要旨集  127年会-  (3)  231  -231  2007/03
  • 新規bisphosphonate系薬剤YM529における骨髄間質細胞でのRANKL発現阻害効果
    西田 升三; 椿 正寛; 加藤 知里; 尾垣 光彦; 谷森 佳弘; 柳江 正嗣; 入交 清博  日本薬学会年会要旨集  127年会-  (2)  145  -145  2007/03
  • 新規bisphosphonate系薬剤YM529におけるRANKL発現阻害によるがん細胞の骨髄内増殖および骨融解の抑制
    西田 升三; 加藤 知里; 椿 正寛; 尾垣 光彦; 谷森 佳弘; 柳江 正嗣; 入交 清博  日本癌学会総会記事  65回-  166  -166  2006/09
  • HMG-CoA還元酵素阻害薬であるstatinのアポトーシス誘導機序の解明
    戸村 隆訓; 椿 正寛; 加藤 知里; 尾垣 光彦; 藤井 克樹; 谷森 佳弘; 柳江 正嗣; 西田 升三  日本癌学会総会記事  65回-  191  -191  2006/09
  • Protein kinase C阻害によるがん細胞の浸潤抑制効果
    椿 正寛; 尾垣 光彦; 加藤 知里; 谷森 佳弘; 柳江 正嗣; 西田 升三  日本癌学会総会記事  65回-  295  -295  2006/09
  • 不死化マウス歯小嚢細胞の特性
    斎藤 正寛; 横井 隆政; 椿本 貴教; 西田 英作; 寺中 敏夫  高次口腔科学研究所年誌  (5)  8  -8  2006/03
  • M Tsubaki; M Yanae; C Kato; Y Tanimori; Y Fujii; S Nishida  JOURNAL OF PHARMACOLOGICAL SCIENCES  100-  126P  -126P  2006
  • C Kato; M Tsubaki; M Hoshino; A Namimatsu; H Uji; M Yanae; S Nishida  JOURNAL OF PHARMACOLOGICAL SCIENCES  100-  71P  -71P  2006
  • Nishida Shozo; Tsubaki Masanobu; Tanimori Yoshihiro  Bulletin of Pharmaceutical Research and Technology Institute  13-  81  -90  2005/03
  • PKC阻害によるTNF-alpha壊死効果増強機序の解明
    西田 升三; 谷森 佳弘; 椿 正寛; 柳江 正嗣; 入交 清博  日本薬学会年会要旨集  125年会-  (3)  77  -77  2005/03
  • Mevastatinによる造血系腫瘍細胞株に対するアポトーシス誘導機序
    柳江 正嗣; 椿 正寛; 谷森 佳弘; 入交 清博; 西田 升三  日本薬学会年会要旨集  125年会-  (3)  81  -81  2005/03
  • 西田升三; 椿正寛; 木下さおり; 吉岡昌平; 垣谷有紀; 藤井克樹; 戸村隆訓; 入交清博  日本癌学会総会記事  62nd-  454  -454  2003/08

Industrial Property Rights

Awards & Honors

  • 日本薬学会近畿支部 日本薬学会近畿支部奨励賞
     
    受賞者: 椿 正寛

Research Grants & Projects

  • がん化学療法誘発末梢神経障害の機序解明と新規治療法の開発
    日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 椿 正寛
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2016/04 -2019/03 
    Author : TSUBAKI Masanobu
     
    I show that oxaliplatin and paclitaxel induces the neuropathy through the activation of PKC/ERK pathway in lumber spinal cords. In addition, PKC and MEK inhibitor suppressed the oxaliplatin- and paclitzxel-induced neuropathy via PKC/ERK pathways. These findings suggest that PKC and MEK inhibitors are potentially useful for oxaliplatin- and paclitaxel-induced neuropathy. As well, these results are summarized as section of presented paper.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : NISHIDA Shozo; TSUBAKI Masanobu; TAKEDA Tomoya
     
    To investigate the underlying mechanisms associated with resistance to imatinib, we established imatinib-resistant chronic myeloid leukemia (CML) cell lines. The resistant cell lines activation of MET. In addition, MET inhibitor reversed the imatinib-resistance of the drug-resistant cell lines. These findings suggest that MET inhibitors are potentially useful as an imatinib-resistance CML agent for the treatment of CML cells. As well, These results are summarized as section of presented paper.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2012/04 -2015/03 
    Author : NISHIDA Shozo; TSUBAKI Masanobu
     
    To investigate the underlying mechanisms associated with resistance to anti-cancer drugs, we established anti-cancer drug-resistant multiple myeloma (MM) cell lines. The resistant cell lines overexpressed MDR1 and survivin, or showed decreased Bim expression through activation of Src. In addition, dasatinib reversed the drug-resistance of the drug-resistant cell lines. These findings suggest that Src inhibitors are potentially useful as an anti-MDR agent for the treatment of malignant tumor cells. As well, These results are summarized as section of presented paper.

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