Radiation and Blocks Induction of Sensitizes Murine Fibroblasts and Human Tumor Cells to The Phosphatidylinositol 3-Kinase Inhibitor Wortmannin

AT cells are extremely sensitive to ionizing radiation. Since the AT gene has homology to phosphatidylinositol 3 kinases(P13-kinases),wortman nm,a specificinhibitorofPI 3-kinase,wasusedtodetermineif P13-kinase activity regulates radiation sensitivity. Human and murine cells exposed to wortmannin alonedid not display significant cytotoxicity. Wortmanmn in combination with radiation was an effective radiosensitizer of munne NIH-3T3 fibroblasts, with a sensitizerenhancementratio of 1.8at 10% survival, and had a similar effect on the human tumor cell lines HeLa, 5W480, andMCF-7.Wortmannininhibitedtheinductionofp5.3DNA binding activity by actinomycin D and radiation and blocked the tran scriptional activation of a p53 CAT reporter gene by actinomycin D. Wortmannin radiosensitizedboth wild-type (NIH-3T3 and MCF-7) and mutant (5W480and HeLa)p53 cells,indicating thatp53 induction wasnot required for radiosensitizationby wortmannin. The resultssuggestthat a wortmannin-sensitive pathway, possibly involving P1 3-klnase activity, may regulatethe responseof the cellsto DNA damage.