title: Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration.
abstract: Auranofin is a gold based drug in clinical use since 1985 for the treatment of rheumatoid arthritis. Beyond its antinflammatory properties, auranofin exhibits other attractive biological and pharmacological actions such as a potent in vitro cytotoxicity and relevant antimicrobial and antiparasitic effects that make it amenable for new therapeutic indications. For instance, auranofin is currently tested as an anticancer agent in four independent clinical trials; yet, its mode of action is highly controversial. With the present study, we explore the effects of auranofin in Saccharomyces cerevisiae and its likely mechanism. Notably, auranofin is reported to induce remarkable yeast growth inhibition. Solid evidence is provided that growth inhibition is the consequence of a direct cytotoxic insult occurring at the mitochondrial level; a profound depression of cell respiration is indeed clearly documented as the main cause of cell death while induction of ROS plays only a secondary role. More in detail, the mitochondrial NADH kinase Pos5 is identified as a primary target for auranofin. The implications of these results are discussed in the frame of current mechanistic knowledge on the cellular effects of auranofin and of its role as a prospective anticancer drug.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, V.le Morgagni, 50-50134 Firenze, Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Gamberi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, V.le Morgagni, 50-50134 Firenze, Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Fiaschi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, V.le Morgagni, 50-50134 Firenze, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Modesti
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3, 50019Sesto Fiorentino (FI), Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Massai
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3, 50019Sesto Fiorentino (FI), Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, V.le Morgagni, 50-50134 Firenze, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Balzi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, V.le Morgagni, 50-50134 Firenze, Italy. Electronic address: francesca.magherini@unifi.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Magherini
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects*
chemical_list: D018501:Antirheumatic Agents; D001310:Auranofin
keywords: Antiproliferation; Auranofin; Pos5 NADH kinase; Respiration inhibition; Yeast