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.

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.

• Authors: Younghyun Lee, Huizi Keiko Li, Aya Masaoka, Shigeaki Sunada, Hirokazu Hirakawa, Akira Fujimori, Jac A Nickoloff, Ryuichi Okayasu
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 121 Issue 1 Pg. 162-168 (10 2016) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 27666928 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Benzodioxoles
• H2AX protein, human
• HSP90 Heat-Shock Proteins
• Histones
• Purines
• Radiation-Sensitizing Agents
• 9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-
• DNA

Topics

• A549 Cells
• Apoptosis (drug effects)
• Benzodioxoles (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• DNA (drug effects, 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, radiotherapy)
• Purines (pharmacology)
• Radiation-Sensitizing Agents (pharmacology)
• Tumor Stem Cell Assay