Radiosensitization effect of poly(ADP‐ribose) polymerase inhibition in cells exposed to low and high liner energy transfer radiation

摘要

Poly(ADP‐ribose) polymerase (PARP)‐1 promotes base excision repair and DNA strand break repair. Inhibitors of PARP enhance the cytotoxic effects of γ‐irradiation and X‐irradiation. We investigated the impact of PARP inhibition on the responses to γ‐irradiation (low liner energy transfer [LET] radiation) and carbon‐ion irradiation (high LET radiation) in the human pancreatic cancer cell line MIA PaCa‐2. Cell survival was assessed by colony formation assay after combination treatment with the PARP inhibitor AZD2281 and single fraction γ‐irradiation and carbon‐ion irradiation (13 and 70 keV/μm [LET 13 and LET 70]). The DNA damage response (DDR) was assessed by pulse field gel electrophoresis, western blotting and flow cytometry. Treatment with a PARP inhibitor enhanced the cytotoxic effect of γ‐irradiation and LET 13 and LET 70 carbon‐ion irradiation. Moreover, the radiosensitization effect was greater for LET 70 than for LET 13 irradiation. Prolonged and increased levels of γ‐H2AX were observed both after γ‐irradiation and carbon‐ion irradiation in the presence of the PARP inhibitor. Enhanced level of phosphorylated‐p53 (Ser‐15) was observed after γ‐irradiation but not after carbon‐ion irradiation. PARP inhibitor treatment induced S phase arrest and enhanced subsequent G2/M arrest both after γ‐irradiation and carbon‐ion irradiation. These results suggest that the induction of S phase arrest through an enhanced DDR and a local delay in DNA double strand break processing by PARP inhibition caused sensitization to γ‐irradiation and carbon‐ion irradiation. Taken together, PARP inhibitors might be applicable to a wide therapeutic range of LET radiation through their effects on the DDR. (Cancer Sci 2012; 103: 1045–1050)