The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks induction of p53 following DNA damage.
AT cells are extremely sensitive to ionizing radiation. Since the AT gene has homology to phosphatidylinositol 3 kinases (PI 3-kinases), wortmannin, a specific inhibitor of PI 3-kinase, was used to determine if PI 3-kinase activity regulates radiation sensitivity. Human and murine cells exposed to wortmannin alone did not display significant cytotoxicity. Wortmannin in combination with radiation was an effective radiosensitizer of murine NIH-3T3 fibroblasts, with a sensitizer enhancement ratio of 1.8 at 10% survival, and had a similar effect on the human tumor cell lines HeLa, SW480, and MCF-7. Wortmannin inhibited the induction of p53 DNA-binding activity by actinomycin D and radiation and blocked the transcriptional activation of a p53 CAT reporter gene by actinomycin D. Wortmannin radiosensitized both wild-type (NIH-3T3 and MCF-7) and mutant (SW480 and HeLa) p53 cells, indicating that p53 induction was not required for radiosensitization by wortmannin. The results suggest that a wortmannin-sensitive pathway, possibly involving PI 3-kinase activity, may regulate the response of the cells to DNA damage.
Joint Center for Radiation Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
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Youmell
D016475:3T3 Cells / Q000187:drug effects* / Q000528:radiation effects*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy; D000730:Androstadienes / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D002470:Cell Survival / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D000077191:Wortmannin
D000730:Androstadienes; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin