(−)-Epigallocatechin 3-Gallate Synthetic Analogues Inhibit Fatty Acid Synthase and Show Anticancer Activity in Triple Negative Breast Cancer

Abstract

(−)-Epigallocatechin 3-gallate (EGCG) is a natural polyphenol from green tea with reported anticancer activity and capacity to inhibit the lipogenic enzyme fatty acid synthase (FASN), which is overexpressed in several human carcinomas. To improve the pharmacological profile of EGCG, we previously developed a family of EGCG derivatives and the lead compounds G28, G37 and G56 were characterized in HER2-positive breast cancer cells overexpressing FASN. Here, diesters G28, G37 and G56 and two G28 derivatives, monoesters M1 and M2, were synthesized and assessed in vitro for their cytotoxic, FASN inhibition and apoptotic activities in MDA-MB-231 triple-negative breast cancer (TNBC) cells. All compounds displayed moderate to high cytotoxicity and significantly blocked FASN activity, monoesters M1 and M2 being more potent inhibitors than diesters. Interestingly, G28, M1, and M2 also diminished FASN protein expression levels, but only monoesters M1 and M2 induced apoptosis. Our results indicate that FASN inhibition by such polyphenolic compounds could be a new strategy in TNBC treatment, and highlight the potential anticancer activities of monoesters. Thus, G28, G37, G56, and most importantly M1 and M2, are anticancer candidates (alone or in combination) to be further characterized in vitro and in vivo.

Current shreds of evidence on the anticancer role of EGCG in triple negative breast cancer: an update of the current state of knowledge

“…Particularly, the monoesters inhibited the growth of MDA-MB-231 cells more than the diesters, and only the monoesters induced the apoptosis detected by poly (ADP-ribose) polymerase (PARP) cleavage. Altogether, these results suggest that these polyphenolic compounds, particularly the monoesters, due to their inhibitory role on FASN, could represent a new strategy for TNBC treatment [26].…”

Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models

“…Both compounds have the ability to internalize and inhibit FASN activity as observed in parental PC9 cells (Figure 4), however G28 was of average 5.5 times more effective than EGCG. We have previously shown the ability of the natural compound EGCG to inhibit FASN activity in wild type EGFR NSCLC cells and different breast cancer subtypes [40,43]. Despite their cytotoxicity, only the synthetic compound significantly reduced FASN activity in GR models (Figure 4).…”

“…To date, many EGCG derivatives have been developed to improve efficacy and increase stability in physiological conditions. Among them, the naphthalene derivative G28 has shown interesting antiproliferative features against sensitive and resistant breast cancer cells [38,43,44].…”

Epigenetic Regulation and Dietary Control of Triple Negative Breast Cancer

“…In vivo, EGCG displays low potency, poor bioavailability, and limited stability. Crous-Maso et al (95) reported on the design and synthesis of a novel collection of polyphenolic compounds, containing two galloyl moieties (3,4,5-trihydroxybenzoyl group) linked by a variable cyclic subunit. These molecules were tested alongside EGCG for their anticancer properties, in particular in TNBC cell models.…”