A PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR WORTMANNIN INDUCES RADIORESISTANT DNA-SYNTHESIS AND SENSITIZES CELLS TO BLEOMYCIN AND IONIZING-RADIATION

ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) have been shown to have sequences homologous to the catalytic domains of m ammalian phosphatidylinositol 3-kinase (PI3-kinase). In order to deter mine the contribution of ATM and DNA-PKcs to the increased sensitivity of cells to DNA-damaging agents observed in the presence of PI3-kinas e inhibitors, we examined the effects of a PI3-kinase inhibitor, wortm annin, on cellular sensitivity to bleomycin (BLM), mitomycin C (MMC), X-irradiation and ultraviolet (UV)-irradiation using 2 human tumor cel l lines (T98G and Al 72), a human fibroblast cell line (LM217), an ata xia telangiectasia (AT) cell line (AT3BISV), a scid murine cell line ( SCF) and a control murine cell line (CBF). Wortmannin sensitized all o f the cells, including AT3BISV and SCF, to BLM and X-irradiation, but: not to MMC or UV-irradiation. Hypersensitivity to BLM and X-irradiati on and normal sensitivity to MMC and UV-irradiation are characteristic phenotypes of both AT and scid mice. DNA-dependent protein kinase (DN A-PK) activity was suppressed by wortmannin to 45-65% of the control v alues 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 T98G and SCF cells, but did not cha nge the DNA synthesis rates after X-irradiation in AT3BISV, Our data s uggest that wortmannin decreases the activities of both the ATM protei n and DNA-PK, indicating that it might be of use as a sensitizing agen t for radiotherapy and chemotherapy. (C) 1998 Wiley-Liss, Inc.