2-phenylethynesulphonamide (PFT-μ) enhances the anticancer effect of the novel hsp90 inhibitor NVP-AUY922 in melanoma, by reducing GSH levels

Abstract

Heat shock proteins (HSPs), are molecular chaperones that assist the proper folding of nascent proteins. This study aims to evaluate the antitumour effects of the hsp90 inhibitor NVP-AUY922 in melanoma, both in vitro and in vivo. Our results show that NVP-AUY922 inhibits melanoma cell growth in vitro, with down regulation of multiple signalling pathways involved in melanoma progression such as NF-KB and MAPK/ERK. However, NVP-AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP-AUY922 and PFT-l, a dual inhibitor of both hsp70 and autophagy, induced a synergistic increase of cell death in vitro, and delayed tumour formation in A375M xenografts. PFT-l depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT-l further enhanced NVP-AUY922-induced cytotoxic effects. These data suggest a potential therapeutic role for NVP-AUY922 used in combination with PFT-l, in melanoma.

This study was suppported by Lliga contra el c ancer de les comarques de Lleida and grants from ISCIII (FIS-PI12/00260 toRMMand RETICSRD12/ 0036/0013 to XMG), from Fundaci o la Marat o de TV3 (FMTV 201331-31 to RMM) and from Generalitat de Catalunya (2014/ SGR138 to XMG) and cofinanced by FEDER ”Una manera de hacer Europa.” Yeramian Andree holds postdoctoral fellowship from AECC. Tumour samples were obtained with the support of Xarxa Catalana de Bancs de Tumours and the Tumour Banc Platform of RTICC (PT13/ 0010/0014). NVP-AUY922 was kindly donated by Novartis. We also thank Dr. Ana€ıs Panosa of the Flow Cytometry Facility at IRBLleida, for her assistance and technical advice.