Radiosensitization of human lung cancer cells by the novel purine-scaffold Hsp90 inhibitor, PU-H71

International Journal of Molecular Medicine
Tatsuya SegawaNobuo Kubota

Abstract

The molecular chaperone heat shock protein 90 (Hsp90) is involved in the maturation and stabilization of a wide range of oncogenic client proteins for oncogenesis and malignant cell proliferation, which renders this protein a promising target in the development of cancer therapeutics. PU-H71 is a purine-scaffold Hsp90 inhibitor with less toxicity in normal cells than in cancer cells. In this study, we examined the in vitro radiosensitizing activity and molecular mechanisms of action of PU-H71 in human lung cancer cell lines. PU-H71 enhanced the sensitivity of the SQ-5 and A549 cancer cells to radiation. When the cancer cells were pre-treated with PU-H71, the repair of DNA double-strand breaks (DSBs) was markedly inhibited after irradiation compared with the cells that were not pre-treated with PU-H71, as evaluated by counting the foci of phosphorylated histone H2AX (γ-H2AX). We further demonstrated that post-irradiation, PU-H71 inhibited Rad51 foci formation, a critical protein for the homologous recombination pathway of DNA DSB repair. These data indicate that targeting Hsp90 with PU-H71 may be novel therapeutic strategy for radioresistant carcinomas.

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Citations

Oct 27, 2015·Biomolecules·Rosa PennisiAlessandra di Masi
Aug 16, 2017·Investigational New Drugs·Giovanna SperanzaShivaani Kummar
Oct 25, 2017·The Journal of Pharmacology and Experimental Therapeutics·Peter J FergusonJames Koropatnick
Jun 1, 2016·Journal of Radiation Research·Huizi Keiko LiTadashi Kamada
Jul 1, 2018·International Journal of Particle Therapy·Younghyun Lee, Ryuichi Okayasu
May 19, 2017·Journal of the National Cancer Institute·Jac A NickoloffRobert Hromas
Sep 19, 2015·Seminars in Radiation Oncology·Henning WillersCläre von Neubeck

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