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.
Radiother Oncol
; 121(1): 162-168, 2016 10.
Article
en En
| MEDLINE
| ID: mdl-27666928
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 ANDMETHODS:
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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Purinas
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Fármacos Sensibilizantes a Radiaciones
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Proteínas HSP90 de Choque Térmico
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Benzodioxoles
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Neoplasias Pulmonares
Límite:
Humans
Idioma:
En
Revista:
Radiother Oncol
Año:
2016
Tipo del documento:
Article
País de afiliación:
Japón