Effect of a phosphatidylinositol 3-kinase inhibitor wortmannin on radiation and bleomycin sensitivities.

ATM和dna依赖性蛋白激酶催化亚基（DNA-PKcs）已被证明具有与哺乳动物磷脂酰肌醇3-激酶（pi3 -激酶）催化结构域同源的序列。为了确定ATM和DNA-PKcs对存在pi3激酶抑制剂的细胞对dna损伤剂的敏感性增加的贡献，我们使用2种人肿瘤细胞系（T98G和A172）、人成纤维细胞系（LM2 17）、失联毛细血管扩张细胞系（AT3BISV）检测了pi3激酶抑制剂wortmannin对贝洛霉素（BLM）、丝裂霉素C （MMC）、x射线照射和紫外线（uv9）照射的细胞敏感性的影响。小鼠细胞系（SCF）和对照小鼠细胞系（CBF）。Wortmannin使包括AT3BISV和SCF在内的所有细胞对BLM和x射线照射敏感，但对MMC或uv照射不敏感。AT和scid小鼠对BLM和x照射超敏，对MMC和uv照射正常敏感。除SCF细胞外，wortmannin将dna依赖性蛋白激酶（DNA-PK）活性抑制至对照组的45-65%。SCF细胞中DNA-PK活性未检测到。Wortmannin还在t98gv和SCF细胞中诱导了抗辐射DNA合成，这是AT的一种细胞表型，但在AT3BISV中，x射线照射后DNA合成率没有改变。我们的数据表明，wortmannin降低了ATM蛋白和DNA-PK的活性，表明它可能用作放疗和化疗的增敏剂。

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.