Fatty acid synthase (FASN) is a key metabolic enzyme. It has relations with catalyzing the terminal steps in long chain saturated fatty acid synthesis. In most human tissues, FASN has low levels. In contrast, FASN expression is significantly elevated in a wide variety of human epithelial cancers, including prostate, breast, endometrium, ovary, lung, colon, and stomach cancers. Several studies using pharmacologic inhibitors against FASN show that blocking FASN activity leads to severe growth arrest and apoptosis in tumor cells. In addition, a wide variety of human cancers overexpresses FASN, making it an attractive target for anticancer therapy. In this study, Cerulenin is a natural product of Cephalosporium caerulens with antifungal activity. It also inhibits growth, is selectively toxic to human cancer cells in vitro. It also retards the development of ovarian cancer xenografts in mice in vivo.
Cerulenin inhibits topoisomerase I catalytic activity and augments SN-38-induced apoptosis. Cerulenin synergistically augments SN-38-induced cytotoxicity. In addition, Cerulenin and SN-38 synergistically induces apoptosis. It also shows inhibitory effects on topoisomerase I. Cerulenin inhibits the catalytic activity of topoisomerase I, at least in part through an intracellular shift toward polyunsaturation. In addition, Cerulenin covalently binds to the catalytic site of FAS and disrupts the condensation reaction of acetyl-COA and malonyl-COA. It inhibits the biosynthesis of fatty acids and sterols in yeast. The Flavonoids quercetin and trans-Chalcone are effective against T. rubrum. The MICs are 125 and 7.5 μg/mL for the wild-type strain and 63 and 1.9 μg/mL for the ABC transporter mutant strain, respectively.
In summary, Cerulenin is a potent FASN inhibitor. It also inhibits topoisomerase I catalytic activity and augments SN-38-induced apoptosis. It has antitumor and antifungal activities.