Data from Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity

Abstract

<div>Abstract<p><b>Purpose:</b> Fatty acid synthase (FASN) is overexpressed in human breast carcinoma. The natural polyphenol (−)-epigallocatechin-3-gallate blocks <i>in vitro</i> FASN activity and leads to apoptosis in breast cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, and <i>in vivo</i>, does not decrease body weight. We synthesized a panel of new polyphenolic compounds and tested their effects on breast cancer models.</p><p><b>Experimental Design:</b> We evaluated the <i>in vitro</i> effects of the compounds on breast cancer cell growth (SK-Br3, MCF-7, and MDA-MB-231), apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase], cell signaling (HER2, ERK1/2, and AKT), and fatty acid metabolism enzymes (FASN and CPT-1). <i>In vivo</i>, we have evaluated their antitumor activity and their effect on body weight in a mice model of BT474 breast cancer cells.</p><p><b>Results:</b> Two compounds potently inhibited FASN activity and showed high cytotoxicity. Moreover, the compounds induced apoptosis and caused a marked decrease in the active forms of HER2, AKT, and ERK1/2 proteins. Interestingly, the compounds did not stimulate CPT-1 activity <i>in vitro</i>. We show evidence that one of the FASN inhibitors blocked the growth of BT474 breast cancer xenografts and did not induce weight loss <i>in vivo</i>.</p><p><b>Conclusions:</b> The synthesized polyphenolic compounds represent a novel class of FASN inhibitors, with <i>in vitro</i> and <i>in vivo</i> anticancer activity, that do not exhibit cross-activation of β-oxidation and do not induce weight loss in animals. One of the compounds blocked the growth of breast cancer xenografts. These FASN inhibitors may represent new agents for breast cancer treatment. (Clin Cancer Res 2009;15(24):7608–15)</p></div>