The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer

// Martin C. Sadowski 1 , Rebecca H. Pouwer 2 , Jennifer H. Gunter 1 , Amy A. Lubik 1,3 , Ronald J. Quinn 2 and Colleen C. Nelson 1,3 1 Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia 2 Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia 3 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada Correspondence: Colleen C. Nelson, email: // Keywords : Triclosan, fatty acid synthase, AMPK, lipid metabolism, C75, orlistat, prostate cancer Received : August 03, 2014 Accepted : September 02, 2014 Published : September 03, 2014 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.