2006 Fiscal Year Final Research Report Summary
New type of cell death mechanism induced by chemotherapeutic agents
| Project/Area Number |
17591083
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto University |
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Principal Investigator |
ADACHI Souichi Kyoto University, Faculty of Medicine, Lecturer, 医学研究科, 講師 (10273450)
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| Co-Investigator(Kenkyū-buntansha) |
UMEDA Katsutsugu Kyoto University, Faculty of Medicine, Associate Professor, 医学研究科, 助手 (80397538)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Cell death by anti-cancer agents / Apoptosis / Autophagy / HDAC inhibitor / Bcr-Abl TK inhibitor |
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| Research Abstract |
A decade of intensive research has revealed several mechanisms that induce programmed cell death (PCD). These mechanisms can be caspase-dependent or caspase-independent. The latter category include caspase-independent apoptosis (CIA), which employs mitochondrial molecules other than cytochrome c, as well other modes of cell death such as autophagic cell death, mitotic catastrophe, or caspase-independent necrosis-like cell death (CIND) We have reported that imatinib mesylate (IM) induced CIND in Bcr-Abl^+ leukemias that is mediated by the serine protease activity of Omi/Htra2. Here we reported the following two interesting papers. (1)Depsipeptide (HDAC inhibitor) induces autophagy in rhabdoid cells both in vitro and in vivo and this autophagy is related with translocation of AIF. We also find that depsipeptide induce autophagy in osteosarcoma cell lines. (2)INNO-406 (a specific dual BCR-ABL/Lyn inhibitor) induce induces programmed cell death (PCD) in Bcr-Abl+ cell lines via both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and CIND, and we observed that the propensity towards CIA or CIND was strongly associated with cellular dependency on caspase activity. Moreover, we found that INNO-406 promotes autophagy. Inhibition of autophagy by chloroquine enhanced both INNO-406 and depsipeptide-induced cell death, indicating the autophagic response as the cell protective mechanism. These findings suggest new insights into the biology and therapy of solid tumors and acute leukemias.
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