title: PU-H71, a novel Hsp90 inhibitor, as a potential cancer-specific sensitizer to carbon-ion beam therapy.
abstract: PU-H71, a heat shock protein 90 (Hsp90) inhibitor, has yielded therapeutic efficacy in many preclinical models and is currently in clinical trials. Carbon-ion radiotherapy (CIRT) has provided successful tumor control; however, there is still room for improvement, particularly in terms of tumor-specific radiosensitization. The Hsp90 inhibitor PU-H71 has been shown to sensitize tumor cells to X-ray radiation. A murine osteosarcoma cell line (LM8) and a normal human fibroblast cell line (AG01522) were treated with PU-H71 before X-ray, 14- or 50-keV/µm carbon-ion beam (C-ion) irradiation. Cell survival and protein expression were evaluated with colony formation and western blot, respectively. Treatment with PU-H71 alone was shown to be non-toxic to both cell lines; however, PU-H71 was shown to significantly sensitize LM8 cells to not only X-ray, but also to C-ion irradiation, while only a minimal sensitizing effect was observed in AG01522 cells. PU-H71 treatment was found to suppress the protein expression levels of Rad51 and Ku70, which are associated with the homologous recombination pathway and the non-homologous end-joining pathway of double-strand break repair. The findings reported here suggest that PU-H71 could be a promising radiosensitizer for CIRT.
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan Graduate School of Medical and Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo, Chiba 263-8522, Japan.
authors.forename: Huizi Keiko
authors.initials: HK
authors.lastname: Li
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan Proton Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8576, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan furusawa@nirs.go.jp.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Furusawa
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage, Chiba 263-8555, Japan Graduate School of Medical and Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo, Chiba 263-8522, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kamada
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology* / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D063193:Heavy Ion Radiotherapy; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014965:X-Rays
chemical_list: D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; D011838:Radiation-Sensitizing Agents; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-
keywords: Hsp90; PU-H71; carbon ion; radiosensitizer