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

Hyun-Jung Moon,So-Eun Jeun,Su-Hoon Lee,Sun-Hee Kim,Hak-Bong Kim,Chi-Dug Kang

doi:10.18632/oncotarget.24130

Abstract

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

Highlights

Selective inhibition of target proteins in cancer cells over their normal counterparts is one of the most critical features of a successful protein inhibitor for clinical applications
To evaluate the potential role of Non-steroidal anti-inflammatory drugs (NSAIDs) in the response of MDR human cancer cells to heat-shock protein 90 (Hsp90) inhibitors, three different MDR cancer cell lines were treated with gradual doses of 17-AAG, a geldanamycin analog Hsp90 inhibitor or AUY922, non-geldanamycin Hsp90 inhibitor, alone or combined with celecoxib (CCB) and determined whether CCB could enhance the susceptibility of MDR cells to Hsp90 inhibitors using MTT assay
To more confirm the combination effect of another NSAID and Hsp90 inhibitor against MDR cells, we examined whether ibuprofen (IBU) could enhance the cytotoxic effect of Hsp90 inhibitor in MDR cells

Summary

Introduction

Selective inhibition of target proteins in cancer cells over their normal counterparts is one of the most critical features of a successful protein inhibitor for clinical applications. The molecular chaperone heat-shock protein 90 (Hsp90) is constitutively overexpressed or activated in cancer cells than normal cells and provides an attractive target for the treatment of cancer [1]. A number of phase II clinical trials have been performed on 17-allylamino-17demethoxy-geldanamycin (17-AAG; a geldanamycin analog) and NVP-AUY922 (hereafter called AUY922; a purine-scaffold derivative and non-geldanamycin analog of 17-AAG) [6,7,8,9]. Their therapeutic benefits were often limited by toxicity and resistance of cancer cells. It has been reported that resistance to Hsp inhibitors is linked to P-glycoprotein (P-gp)-mediated efflux and to the induction of heat shock proteins (Hsps) [10, 11], which is caused by the disruption of Hsp with heat shock factor 1 (HSF1)

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Results

Conclusion