Loss of the cell cycle regulatory protein p53 or overexpression of the anti-apoptotic protein bcl-2 is associated with resistance of several types of cancer cells to radiation. The anti-tumor effects of flavopiridol are exerted by inducing cell cycle arrest and apoptosis. Therefore, we hypothesized that flavopiridol would enhance the cytotoxic effects of radiation in tumor cells containing a mutated p53 protein (A172/mp53) or overexpressing bcl-2 (HeLa/bcl-2 cells). The effects of flavopiridol on radiosensitivity were investigated using the colony formation assay and apoptotic cells were quantified by flow cytometric assay. When compared with parent wild-type cells, both cell types were more resistant to radiation. Flavopiridol increased the cytotoxic effects of radiation in both mutant cells, but not in their parent cells. The dose modification factors at 37% survival in those cells were about 1.3 and 1.7, respectively. Additional treatment with flavopiridol inhibited sublethal damage repair (SLDR) in response to radiation but did not significantly increase radiation-induced apoptosis in either cell type. These results suggest that flavopiridol may enhance the cytotoxic effect of radiation on tumor cells with mutant p53 or Bcl-2 overexpression. Therefore, a combination of radiotherapy and flavopiridol may be a therapeutically useful approach for treating tumors with those genetic alterations.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]