| Project/Area Number |
16390420
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | FUJITA HEALTH UNIVERSITY (2006)
Keio University (2004-2005) |
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Principal Investigator |
HIROSE Yuichi FUJITA HEALTH UNIVERSITY, School of Medicine, Associate Professor, 医学部, 助教授 (60218849)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥11,300,000 (Direct Cost: ¥11,300,000)
Fiscal Year 2006: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥4,300,000 (Direct Cost: ¥4,300,000)
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| Keywords | glioma / Akt pathway / DNA alkylating agents / 90kD heat shock protein / UCN-01 / G2 checkpoint / chemosensitization / 90kD Heat shock protein / Geldanamycin / 17-AAG / Radicicol / 細胞周期 |
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| Research Abstract |
Inhibition of the G2 checkpoint has been previously shown to sensitize glioma cells to methylating agent-induced mitotic catastrophe and cell death. Because Akt overexpression suppresses the G2 checkpoint in cells exposed to ionizing radiation, and because glioblastomas frequently have high levels of Akt activation, we examined the role Akt may play in the G2 arrest and toxicity induced by chemotherapeutic DNA-alkylating agents (DAA). U87 human glioma cells were retrovirally infected with a tamoxifen (TAM)-activated Akt construct, exposed to DAA or TAM+DAA, and assayed for components of the G2 arrest pathway and survival. The results showed that Akt activation suppresses activation of the G2 checkpoint, while at the same time suppressing DAA-induced cell death, senescence, and mitotic catastrophe in cells that avoid G2 arrest. Next we investigated the effect of two kinds of compound that potentially suppress Akt. One is 90-kD heat shock protein (Hsp90) inhibitor and another is staurosp
… More
orin derivative UCN-01.
Previous studies revealed that Hsp90 is expressed at higher levels in human neoplastic tissues including gliomas than in normal tissues. We hypothesized that Hsp90 inhibitors might act as antitumor agents against gliomas and potentiate the cytotoxicity of DNA-damaging agents because it participates in the functions of its client proteins including Akt. In the present study, we found that the Hsp90 inhibitors reduced the clonogenicity of U87MG human glioma cells and potentiated the cytotoxicity of DAA on human glioma cells at a lower concentration (10 nM). We conclude that Hsp90-targeted therapy may provide an effective strategy for the chemosensitization of human gliomas.
UCN-01 inhibited G2 checkpoint in DAA-treated glioma cells at lower concentration while Akt inhibition required higher concentration of this compound.
The Akt pathway and G2 checkpoint may therefore represent a new target for the sensitization of gliomas, and in particular Akt overexpressing glioblastomas, to chemotherapeutic DNA-alkylating agents. Less
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