Haruo Miyata1, Tadashi Ashizawa1, Akira Iizuka1, Ryota Kondou1, Chizu Nonomura1, Takashi Sugino2, Kenichi Urakami3, Akira Asai4, Nakamasa Hayashi5, Koichi Mitsuya5, Yoko Nakasu5, Ken Yamaguchi6, Yasuto Akiyama7,5. 1. Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Shizuoka, Japan. 2. Division of Pathology, Shizuoka Cancer Center Hospital, Shizuoka, Japan. 3. Cancer Diagnostics Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Shizuoka, Japan. 4. Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. 5. Division of Neurosurgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan. 6. Office of the President, Shizuoka Cancer Center Hospital, Shizuoka, Japan. 7. Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Shizuoka, Japan y.akiyama@scchr.jp.
Abstract
BACKGROUND: Temozolomide-resistant (TMZ-R) glioblastoma is very difficult to treat, and a novel approach to overcome resistance is needed. MATERIALS AND METHODS: The efficacy of a combination treatment of STAT3 inhibitor, STX-0119, with rapamycin was investigated against our established TMZ-resistant U87 cell line. RESULTS: The growth-inhibitory effect of the combination treatment was significant against the TMZ-R U87 cell line (IC50: 78 μM for STX-0119, 30.5 μM for rapamycin and 11.3 μM for combination of the two). Western blotting analysis demonstrated that the inhibitory effect of STX-0119 on S6 and 4E-BP1 activation through regulation of YKL-40 expression occurred in addition to the inhibitory effect of rapamycin against the mTOR pathway. CONCLUSION: These results suggest that the STAT3 pathway is associated with the mTOR downstream pathway mediated by YKL-40 protein, and the combination therapy of the STAT3 inhibitor and rapamycin could be worth developing as a novel therapeutic approach against TMZ-resistant relapsed gliomas. Copyright
BACKGROUND:Temozolomide-resistant (TMZ-R) glioblastoma is very difficult to treat, and a novel approach to overcome resistance is needed. MATERIALS AND METHODS: The efficacy of a combination treatment of STAT3 inhibitor, STX-0119, with rapamycin was investigated against our established TMZ-resistant U87 cell line. RESULTS: The growth-inhibitory effect of the combination treatment was significant against the TMZ-R U87 cell line (IC50: 78 μM for STX-0119, 30.5 μM for rapamycin and 11.3 μM for combination of the two). Western blotting analysis demonstrated that the inhibitory effect of STX-0119 on S6 and 4E-BP1 activation through regulation of YKL-40 expression occurred in addition to the inhibitory effect of rapamycin against the mTOR pathway. CONCLUSION: These results suggest that the STAT3 pathway is associated with the mTOR downstream pathway mediated by YKL-40 protein, and the combination therapy of the STAT3 inhibitor and rapamycin could be worth developing as a novel therapeutic approach against TMZ-resistant relapsed gliomas. Copyright
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