pifithrin-mu and Neoplasm-Metastasis

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.

Topics: Animals; Antineoplastic Agents; Autophagy; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Glutathione; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Isoxazoles; MAP Kinase Signaling System; Melanoma; Mice, SCID; Neoplasm Metastasis; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Resorcinols; RNA, Messenger; Skin; Sulfonamides; Xenograft Model Antitumor Assays