Younghyun Lee1, Huizi Keiko Li2, Aya Masaoka1, Shigeaki Sunada3, Hirokazu Hirakawa1, Akira Fujimori1, Jac A Nickoloff4, Ryuichi Okayasu5. 1. Dept. of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, Japan. 2. Dept. of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, Japan; Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Japan. 3. Dept. of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, Japan; Department of Nuclear Engineering and Management, School of Engineering, The University of Tokyo, Japan. 4. Department of Environmental and Radiological Health Sciences, Colorado State University, USA. 5. Dept. of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, Japan. Electronic address: okayasu.ryuichi@qst.go.jp.
Abstract
BACKGROUND AND PURPOSE: PU-H71 is a purine-scaffold Hsp90 inhibitor developed to overcome limitations of conventional Hsp90 inhibitors. This study was designed to investigate the combined effect of PU-H71 and heavy ion irradiation on human tumor and normal cells. MATERIALS AND METHODS: The effects of PU-H71 were determined by monitoring cell survival by colony formation, and DNA double-strand break (DSB) repair by γ-H2AX foci and immuno-blotting DSB repair proteins. The mode of cell death was evaluated by sub-G1 DNA content (as an indicator for apoptosis), and mitotic catastrophe. RESULTS: PU-H71 enhanced heavy ion irradiation-induced cell death in three human cancer cell lines, but the drug did not radiosensitize normal human fibroblasts. In irradiated tumor cells, PU-H71 increased the persistence of γ-H2AX foci, and it reduced RAD51 foci and phosphorylated DNA-PKcs, key DSB repair proteins involved in homologous recombination (HR) and non-homologous end joining (NHEJ). In some tumor cell lines, PU-H71 altered the sub-G1 cell fraction and mitotic catastrophe following carbon ion irradiation. CONCLUSION: Our results demonstrate that PU-H71 sensitizes human cancer cells to heavy ion irradiation by inhibiting both HR and NHEJ DSB repair pathways. PU-H71 holds promise as a radiosensitizer for enhancing the efficacy of heavy ion radiotherapy.
BACKGROUND AND PURPOSE:PU-H71 is a purine-scaffold Hsp90 inhibitor developed to overcome limitations of conventional Hsp90 inhibitors. This study was designed to investigate the combined effect of PU-H71 and heavy ion irradiation on humantumor and normal cells. MATERIALS AND METHODS: The effects of PU-H71 were determined by monitoring cell survival by colony formation, and DNA double-strand break (DSB) repair by γ-H2AX foci and immuno-blotting DSB repair proteins. The mode of cell death was evaluated by sub-G1 DNA content (as an indicator for apoptosis), and mitotic catastrophe. RESULTS:PU-H71 enhanced heavy ion irradiation-induced cell death in three humancancer cell lines, but the drug did not radiosensitize normal human fibroblasts. In irradiated tumor cells, PU-H71 increased the persistence of γ-H2AX foci, and it reduced RAD51 foci and phosphorylated DNA-PKcs, key DSB repair proteins involved in homologous recombination (HR) and non-homologous end joining (NHEJ). In some tumor cell lines, PU-H71 altered the sub-G1 cell fraction and mitotic catastrophe following carbon ion irradiation. CONCLUSION: Our results demonstrate that PU-H71 sensitizes humancancer cells to heavy ion irradiation by inhibiting both HR and NHEJ DSB repair pathways. PU-H71 holds promise as a radiosensitizer for enhancing the efficacy of heavy ion radiotherapy.
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