title: Radiosensitization effect of poly(ADP-ribose) polymerase inhibition in cells exposed to low and high liner energy transfer radiation.
abstract: 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.
authors.affiliation: Division of Genome Stability Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hirai
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shirai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okayasu
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sasai
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005720:Gamma Rays; D006657:Histones / Q000096:biosynthesis; D006801:Humans; D018499:Linear Energy Transfer; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D010766:Phosphorylation / Q000528:radiation effects; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011838:Radiation-Sensitizing Agents; D059807:S Phase Cell Cycle Checkpoints / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib