Poly(ADP-ribose) polymerase (PARP)-1 promotes base excision repair and DNA strand break repair. Inhibitors of PARP enhance the cytotoxic effects of gamma- and X-irradiation. We investigated the impact of PARP inhibition on the responses to gamma-irradiation (low LET (liner energy transfer) 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 gamma-irradiation and carbon-ion irradiation (LET 13 and 70 keV/um). The DNA damage response (DDR) was assessed by pulse field gel electrophoresis (PFGE), Western blotting and flow cytometry. Treatment with a PARP inhibitor enhanced the cytotoxic effect of gamma-, 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 gamma-H2AX were observed both after gamma- and carbon-ion irradiation in the presence of the PARP inhibitor. Enhanced level of phosphorylated-p53 (Ser-15) was observed after gamma-irradiation but not after carbon-ion irradiation. PARP inhibitor treatment induced S phase arrest and enhanced subsequent G2/M arrest both after gamma- 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 gamma- 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
