title: 2-phenylethynesulphonamide (PFT-μ) enhances the anticancer effect of the novel hsp90 inhibitor NVP-AUY922 in melanoma, by reducing GSH levels.
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.
authors.affiliation: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova HUAV, IRBLleida, University of Lleida, Lleida, Spain.
authors.forename: Andree
authors.initials: A
authors.lastname: Yeramian
authors.affiliation: Department of Dermatology, Hospital Universitari Arnau de Vilanova, IRB-Lleida, University of Lleida, Lleida, Spain.
authors.forename: Alvar
authors.initials: A
authors.lastname: Vea
authors.affiliation: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova HUAV, IRBLleida, University of Lleida, Lleida, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Benítez
authors.affiliation: Developmental and Oncogenic Signalling Group, IRBLleida, Lleida, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Ribera
authors.affiliation: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova HUAV, IRBLleida, University of Lleida, Lleida, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Domingo
authors.affiliation: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova HUAV, IRBLleida, University of Lleida, Lleida, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.affiliation: Biostatistics Unit, Hospital Universitari Arnau de Vilanova, IRB-Lleida, University of Lleida, Lleida, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova HUAV, IRBLleida, University of Lleida, Lleida, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Maiques
authors.affiliation: Biostatistics Unit, Hospital Universitari Arnau de Vilanova, IRB-Lleida, University of Lleida, Lleida, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Valls
authors.affiliation: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova HUAV, IRBLleida, University of Lleida, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
authors.affiliation: Department of Immunology, Hospital Clinic, Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Vilella
authors.affiliation: Departament de Ciencies Mediques basiques, IRBlleida, University of Lleida, Lleida, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cabiscol
authors.affiliation: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova HUAV, IRBLleida, University of Lleida, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: Department of Dermatology, Hospital Universitari Arnau de Vilanova, IRB-Lleida, University of Lleida, Lleida, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Marti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C545747:2-phenylacetylenesulfonamide; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D016328:NF-kappa B; D012333:RNA, Messenger; D012118:Resorcinols; D013449:Sulfonamides; D005978:Glutathione
keywords: GSH; PFT-μ; autophagy; endoplasmic reticulum; hsp; melanoma