Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity

Abstract

Purpose: Fatty acid synthase (FASN) is overexpressed in human breast carcinoma.The natural polyphenol (-)-epigallocatechin-3-gallate blocks in vitro FASN activity and leads to apoptosis in breast cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, and in vivo, does not decrease body weight. We synthesized a panel of new polyphenolic compounds and tested their effects on breast cancer models. Experimental Design: We evaluated the in vitro 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). In vivo, we have evaluated their antitumor activity and their effect on body weight in a mice model of BT474 breast cancer cells. Results: 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 in vitro. We show evidence that one of the FASN inhibitors blocked the growth of BT474 breast cancer xenografts and did not induce weight loss in vivo. Fatty acid synthase (E.C.2.3.1.85; FASN) is a lipogenic enzyme which catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA, and NADPH precursors (1). FASN expression is generally low or undetectable in human tissues other than the liver and adipose tissue, and nonmalignant cells preferentially use circulating dietary fatty acids for the synthesis of new structural lipids. In contrast, high levels of FASN expression have been observed in breast cancer (2) and other human carcinomas (reviewed in ref.3). Importantly, several reports have shown that FASN expression levels correlate with tumor progression, aggressiveness, and metastasis, and are found elevated in the serum of patients with cancer

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…Fatty acid synthase (FASN) showed activity in promoting tumorigenesis by activating HER2/PI3K/AKT/mTOR and MAPK signaling pathways (93)(94)(95). EGFR and pEGFR increased in trastuzumab resistant cells noticeably, which was consistent with the study of Wu et al (92).…”

Blocking fatty acid synthase inhibits tumor progression of human osteosarcoma by regulating the human epidermal growth factor receptor 2/phosphoinositide 3-kinase/protein kinase B signaling pathway in xenograft models

“…A previous study demonstrated that small interfering RNA silencing of FASN decreased the PI3K/Akt/NF-κB signaling pathway in vitro (32); however, the mechanism (s) responsible for the inhibition of Akt activity due to the downregula tion of FASN have not been investigated. A study by Puig et al (35) revealed that inhibition of FASN resulted in a marked decrease in the active forms of the HER2 protein. FASN-mediated lipogenesis produces phospholipids that are incorporated into cell membranes and partitioned into lipid rafts, which accommodate HER proteins and form signaling platforms.…”

Blockade of Fatty Acid Synthase Induces Ubiquitination and Degradation of Phosphoinositide-3-Kinase Signaling Proteins in Ovarian Cancer

“…The FASN inhibitory drug C75 has been described as a malonyl-CoA analogue and is known to concomitantly activate fatty acid degradation by antagonizing the allosteric inhibitory effect of malonyl-CoA on carnitine palmitoyltransferase-I (CPT-I), the major rate-limiting enzyme for long-chain fatty acid oxidation (18)(19)(20). Therefore, we examined whether the observed C75-induced effects on PI3K downstream protein expression, phosphorylation, and stability were indeed because of blockade of FASN and not because of concurrent activation of CPT-I by transiently transfecting A2780 cells with a set of 4 different FASNspecific siRNAs.…”