The purine scaffold Hsp90 inhibitor PU-H71 sensitizes cancer cells to heavy ion radiation by inhibiting DNA repair by homologous recombination and non-homologous end joining

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• 作者：Younghyun Lee^a ; Huizi Keiko Li^a ; ^b ; Aya Masaoka^a ; Shigeaki Sunada^a ; ^c ; Hirokazu Hirakawa^a ; Akira Fujimori^a ; Jac A. Nickoloff^d ; Ryuichi Okayasu^a ; ^{okayasu.ryuichi@qst.go.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PU-H71 ; Hsp90 ; Heavy ion radiotherapy ; Radiosensitization ; DNA repair
• 刊名：Radiotherapy and Oncology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：121
• 期：1
• 页码：162-168
• 全文大小：1209 K

文摘

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.