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Title: Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells

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 protonmore » 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. - Highlights: • Effective radiosensitizers for particle radiation therapy have not been reported. • PARP inhibitor treatment radiosensitized after proton beam irradiation. • The sensitization at Bragg peak was greater than that at entrance region. • DSB induction and G2/M arrest is involved in the sensitization mechanism.« less
Authors:
 [1] ;  [2] ; ;  [3] ; ;  [4] ;  [5] ;  [3] ;  [2]
  1. Department of Radiation Oncology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo (Japan)
  2. (Japan)
  3. Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan)
  4. Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima-shi, Hiroshima (Japan)
  5. International Open Laboratory, National Institute of Radiological Science, Chiba-shi, Chiba (Japan)
Publication Date:
OSTI Identifier:
22606211
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 478; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADP; BRAGG CURVE; CARBON; CARBON IONS; DNA; EXCISION REPAIR; HEAVY IONS; INHIBITION; IONIZING RADIATIONS; IRRADIATION; LET; LUNGS; NEOPLASMS; PANCREAS; PROTON BEAMS; RADIOSENSITIZERS; RADIOTHERAPY; RIBOSE