title: Repositioning proton pump inhibitors as anticancer drugs by targeting the thioesterase domain of human fatty acid synthase.
abstract: Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clinical use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compounds may be acting on cancer cells.
authors.affiliation: Department of Pharmacology and Toxicology, ‡Department of Medicine, and §IU Simon Cancer Center, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Fako
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.forename: Beth
authors.initials: B
authors.lastname: Pflug
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Liu
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058492:Drug Repositioning; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D064747:Lansoprazole / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D010170:Palmitoyl-CoA Hydrolase / Q000037:antagonists & inhibitors*; D017434:Protein Structure, Tertiary; D054328:Proton Pump Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D019308:Palmitic Acid; D064429:Fatty Acid Synthases; D010170:Palmitoyl-CoA Hydrolase