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The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer
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 antibacte...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253440/ https://www.ncbi.nlm.nih.gov/pubmed/25313139 |
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author | Sadowski, Martin C. Pouwer, Rebecca H. Gunter, Jennifer H. Lubik, Amy A. Quinn, Ronald J. Nelson, Colleen C. |
author_facet | Sadowski, Martin C. Pouwer, Rebecca H. Gunter, Jennifer H. Lubik, Amy A. Quinn, Ronald J. Nelson, Colleen C. |
author_sort | Sadowski, Martin C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4253440 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-42534402014-12-03 The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer Sadowski, Martin C. Pouwer, Rebecca H. Gunter, Jennifer H. Lubik, Amy A. Quinn, Ronald J. Nelson, Colleen C. Oncotarget Research Paper 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. Impact Journals LLC 2014-09-03 /pmc/articles/PMC4253440/ /pubmed/25313139 Text en Copyright: © 2014 Sadowski et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Sadowski, Martin C. Pouwer, Rebecca H. Gunter, Jennifer H. Lubik, Amy A. Quinn, Ronald J. Nelson, Colleen C. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer |
title | The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer |
title_full | The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer |
title_fullStr | The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer |
title_full_unstemmed | The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer |
title_short | The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer |
title_sort | fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253440/ https://www.ncbi.nlm.nih.gov/pubmed/25313139 |
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