title: Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells.
abstract: The poly(ADP-ribose) polymerase (PARP)-1 regulates DNA damage responses and promotes base excision repair. PARP inhibitors have been shown to enhance the cytotoxicity of ionizing radiation in various cancer cells and animal models. We have demonstrated that the PARP inhibitor (PARPi) AZD2281 is also an effective radiosensitizer for carbon-ion radiation; thus, we speculated that the PARPi could be applied to a wide therapeutic range of linear energy transfer (LET) radiation as a radiosensitizer. Institutes for biological experiments using proton beam are limited worldwide. This study was performed as a cooperative research at heavy ion medical accelerator in Chiba (HIMAC) in National Institute of Radiological Sciences. HIMAC can generate various ion beams; this enabled us to compare the radiosensitization effect of the PARPi on cells subjected to proton and carbon-ion beams from the same beam line. After physical optimization of proton beam irradiation, the radiosensitization effect of the PARPi was assessed in the human lung cancer cell line, A549, and the pancreatic cancer cell line, MIA PaCa-2. The effect of the PARPi, AZD2281, on radiosensitization to Bragg peak was more significant than that to entrance region. The PARPi increased the number of phosphorylated H2AX (γ-H2AX) foci and enhanced G2/M arrest after proton beam irradiation. This result supports our hypothesis that a PARPi could be applied to a wide therapeutic range of LET radiation by blocking the DNA repair response.
authors.affiliation: Department of Radiation Oncology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan; Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hirai
authors.affiliation: Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Saito
authors.affiliation: Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.affiliation: Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima-shi, Hiroshima, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima-shi, Hiroshima, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Nishio
authors.affiliation: International Open Laboratory, National Institute of Radiological Science, Chiba-shi, Chiba, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okayasu
authors.affiliation: Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: mmasutan@nagasaki-u.ac.jp.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D061766:Proton Therapy / Q000379:methods*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C531550:olaparib
keywords: PARP; Particle radiation; Proton beam; Proton therapy; Radiosensitizer