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

Pigment Cell Melanoma Res. 2016 May;29(3):352-71. doi: 10.1111/pcmr.12472.

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-ĸB and MAPK/ERK. However, NVP-AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP-AUY922 and PFT-μ, 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-μ depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT-μ further enhanced NVP-AUY922-induced cytotoxic effects. These data suggest a potential therapeutic role for NVP-AUY922 used in combination with PFT-μ, in melanoma.

Keywords: GSH; PFT-μ; autophagy; endoplasmic reticulum; hsp; melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Autophagy / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Endoplasmic Reticulum Stress / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glutathione / metabolism*
  • HSP70 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Isoxazoles / pharmacology
  • Isoxazoles / therapeutic use*
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Mice, SCID
  • NF-kappa B / metabolism
  • Neoplasm Metastasis
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Resorcinols / pharmacology
  • Resorcinols / therapeutic use*
  • Skin / drug effects
  • Skin / metabolism
  • Skin / pathology
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*
  • Xenograft Model Antitumor Assays

Substances

  • 2-phenylacetylenesulfonamide
  • 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
  • Antineoplastic Agents
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Isoxazoles
  • NF-kappa B
  • RNA, Messenger
  • Resorcinols
  • Sulfonamides
  • Glutathione