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Clin Cancer Res. 2009 Dec 15;15(24):7608-7615.

Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity.

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Authors' Affiliations: Institut Català d'Oncologia and Institut d'Investigació Biomèdica de Girona, Bioquímica i Biologia Molecular, Facultat de Ciències, Universitat de Girona, Girona, Spain; Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, M.D. Anderson Cancer Center España, Madrid, Spain; Institut Català d'Oncologia and Institut d'Investigació Biomèdica de Bellvitge, and Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona, Barcelona, Spain.

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.

CONCLUSIONS:

The synthesized polyphenolic compounds represent a novel class of FASN inhibitors, with in vitro and in vivo anticancer activity, that do not exhibit cross-activation of beta-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).

PMID:
20008854
DOI:
10.1158/1078-0432.CCR-09-0856
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