title: The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer.
abstract: Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Sadowski
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Pouwer
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Gunter
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane,Australia. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Lubik
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Quinn
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane,Australia. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
mesh_terms: D016475:3T3 Cells; D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D058492:Drug Repositioning; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors*; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D000077403:Orlistat; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000494:pharmacology*
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D000891:Anti-Infective Agents, Local; D000970:Antineoplastic Agents; D054872:Fatty Acid Synthesis Inhibitors; D007783:Lactones; D014260:Triclosan; D000077403:Orlistat; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D015107:4-Butyrolactone