IKEHATA Hironobu Tohoku University School of Medicine, Research Associate, 医学部, 助手 (90250737)
YAMADA Shyogo Tohoku University School of Medicine, Professor, 医学部, 教授 (60158194)
ONO Tetsuya Tohoku University School of Medicine, Professor, 医学部, 教授 (00107509)
|Budget Amount *help
¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1998 : ¥1,300,000 (Direct Cost : ¥1,300,000)
ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) have been shown to have sequences homologous to the catalytic domains of mammalian phosphatidylinositol 3-kinase (PI3-kinase). In order to determine the contribution of ATM and DNA-PKcs to the increased sensitivity of cells to DNA-damaging agents observed in the presence of PI3-kinase inhibitors, we examined the effects of a PI3-kinase inhibitor, wortmannin, on cellular sensitivity to belomycin (BLM), mitomycin C (MMC), X-irradiation and ultraviolet (UV9-irradiation using2 human tumor cell lines (T98G and A172), a human fibroblast cell line (LM2 17), an ataxia telangiectasia (AT) cell line (AT3BISV), a scid murine cell line (SCF) and control murine cell line (CBF). Wortmannin sensitized all of the cells, including AT3BISV and SCF, to BLM and X-irradiation, but not to MMC or UV-irradiation. Hypersensitivity to BLM and X-irradiation and normal sensitivity to MMC and UV-irradiation are characteristic phenotypes of both AT and scid mice. DNA-dependent protein kinase (DNA-PK) activity was suppressed by wortmannin to 45-65% of the control values in all of the cells except SCF, in which DNA-PK activity was not detected. Wortmannin also induced radioresistant DNA synthesis, which is a cellular phenotype of AT, in T98Gand SCF cells, but did not change the DNA synthesis rates after X-irradiation in AT3BISV.Our data Suggest that wortmannin decreases the activities of both the ATM protein and DNA-PK, indicating that it might be of use as a sensitizing agent for radiotherapy and chemotherapy.