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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Blotting, Western
  • Cell Line, Tumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • In Situ Nick-End Labeling
  • Melanoma / enzymology
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Microscopy, Electron, Scanning

Substances

  • HSP90 Heat-Shock Proteins
  • Heterocyclic Compounds, 4 or More Rings
  • SNX 2112