Sensitization of multidrug-resistant cancer cells to Hsp90 inhibitors by NSAIDs-induced apoptotic and autophagic cell death.

摘要: NSAIDs (non-steroidal anti-inflammatory drugs) have potential use as anticancer agents, either alone or in combination with other cancer therapies. We found that including celecoxib (CCB) and ibuprofen (IBU) significantly potentiated the cytotoxicity of Hsp90 inhibitors human multidrug-resistant (MDR) cells expressing high levels mutant p53 (mutp53) protein P-glycoprotein (P-gp), reversed inhibitor resistance caused by activation heat shock factor 1 (HSF1) up-regulation proteins (Hsps) P-gp. Inhibition Akt/mTOR STAT3 pathways CCB induced autophagy, which promoted degradation mutp53, one client proteins, subsequently down-regulated HSF1/Hsps autophagy prevented mutp53 CCB-induced apoptosis, inhibition caspase-3-mediated apoptotic pathway Z-DEVD-FMK did not completely block cell death MDR cells, suggesting autophagic may contribute to cells. Furthermore, IBU suppressed inhibitor-induced HSF1/Hsp70/P-gp activity expression Our results suggest can be used chemosensitizers reverse via induction apoptosis autophagy. These might enable lower, less toxic doses facilitate design practically applicable, novel therapy for treatment cancer.