Cancer Lett. 2012 May 28;318(2):180-8. doi: 10.1016/j.canlet.2011.12.015. Epub 2011 Dec 17.

SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells.

Liu KS, Liu H, Qi JH, Liu QY, Liu Z, Xia M, Xing GW, Wang SX, Wang YF.

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Guangzhoujinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China.

Abstract

SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-2112 in A-375 cells. SNX-2112 induced the degradation of multiple Hsp90 client proteins, activated both the mitochondrial-mediated and death receptor-mediated apoptotic pathways, downregulated Bcl-2 and Bcl-xL, upregulated Bid, cleaved caspase-9, caspase-7, caspase-3 and PARP, and activated caspase-8. The general caspase inhibitor, z-VAD-fmk, did not completely abolish SNX-2112-induced cell death. SNX-2112 induced autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and autophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent.

PMID:: 22182451; [PubMed - indexed for MEDLINE]

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