RRC ID 52012
Author Lee Y, Li HK, Masaoka A, Sunada S, Hirakawa H, Fujimori A, Nickoloff JA, Okayasu R.
Title 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.
Journal Radiother Oncol
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.
Volume 121(1)
Pages 162-168
Published 2016-10
DOI 10.1016/j.radonc.2016.08.029
PII S0167-8140(16)34293-1
PMID 27666928
PMC PMC5110220
MeSH A549 Cells Apoptosis / drug effects Benzodioxoles / pharmacology* Cell Death / drug effects Cell Line, Tumor DNA / drug effects DNA / radiation effects DNA Breaks, Double-Stranded DNA End-Joining Repair / drug effects DNA Repair / drug effects HSP90 Heat-Shock Proteins / antagonists & inhibitors* HeLa Cells Heavy Ion Radiotherapy Histones / metabolism Homologous Recombination / drug effects Humans Lung Neoplasms / drug therapy* Lung Neoplasms / radiotherapy* Purines / pharmacology* Radiation-Sensitizing Agents / pharmacology* Tumor Stem Cell Assay
IF 4.942
Resource
Human and Animal Cells SQ5 (RCB0110)