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.
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Autophagy / drug effects
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Resistance, Neoplasm / drug effects
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Drug Synergism
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Endoplasmic Reticulum Stress / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Glutathione / metabolism*
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HSP70 Heat-Shock Proteins / metabolism
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Isoxazoles / pharmacology
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Isoxazoles / therapeutic use*
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MAP Kinase Signaling System / drug effects
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Melanoma / drug therapy*
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Melanoma / genetics
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Melanoma / metabolism*
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Mice, SCID
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NF-kappa B / metabolism
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Neoplasm Metastasis
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Oxidation-Reduction / drug effects
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Oxidative Stress / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Resorcinols / pharmacology
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Resorcinols / therapeutic use*
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Skin / drug effects
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Skin / metabolism
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Skin / pathology
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use*
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Xenograft Model Antitumor Assays
Substances
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2-phenylacetylenesulfonamide
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5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
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Antineoplastic Agents
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HSP70 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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Isoxazoles
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NF-kappa B
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RNA, Messenger
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Resorcinols
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Sulfonamides
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Glutathione