HSP90 inhibitor ganetespib enhances the sensitivity of lung cancer cell to cis-diamminedichloroplatinum
Objective: To investigate the potential effects of HSP90 inhibitor ganetespib in the sensitization of cis-diamminedichloroplatinum (DDP) through down regulation of DNA repair protein BRCA1 and RAD51. Methods: Many aspects of the inhibition were studied. Western blot was used to detect the expression of BRCA1 and RAD51 in A549 and H1975 cell. Intracellularly, the formation of γ-H2AX and RAD51 foci were detected by immunofluorescence staining. Apoptotic cells were analyzed by Flow cytometry. Cell proliferation was examined by using cell counting kit-8 (CCK-8), and the combined drug interaction was analyzed using the median-effect method. Lastly, in vivo anti-tumor activity was evaluated in A549 xenograft SCID mice. Results: The expressions of BRCA1 and RAD51 were significantly down regulated by ganetespib treatment. Combined treatment of ganetespib and DDP induced significantly less RAD51 foci than DDP treatment alone and also induced more apoptosis than DDP treatment alone. The combination of ganetespib and DDP in A549 xenograft model resulted in a superior therapeutic response compared to treatment with just single-agent DDP. Conclusion: Ganetespib demonstrated the ability to down regulate the expression of DNA repair proteins in lung cancer cell and enhance the sensitivity to DDP.