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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.
Highlights
Breast cancer is the most widespread cancer in women worldwide [1]
We synthesized diesters G28, G37 and G56 together with G28-derived monoesters M1 and M2, and we evaluated their cytotoxicity and capacity to inhibit fatty acid synthase (FASN) activity and to induce apoptosis in the MDA-MB-231 Triple-negative breast cancer (TNBC) cell model
The synthesis of diesters G28, G37 and G56 [21,22], and of monoesters M1 and M2 [26] was performed performed using procedures adapted from previously described protocols (Supplementary using procedures adapted from previously described protocols (Supplementary Materials) [23,26,27]
Summary
Breast cancer is the most widespread cancer in women worldwide [1]. mortality has diminished in recent years owing to the programs of early diagnosis and to the improvement in treatment, this disease is still the first cause of death in women. TNBC comprises about 15–20% of all breast cancers diagnosed It tends to have an aggressive clinical course and to metastasize, resulting in early relapse and poor overall survival [2]. Patients with TNBC do not benefit from the targeted therapies used in other breast cancer subtypes, such as hormonal and anti-HER2 receptor therapies, leaving systemic cytotoxic chemotherapy as the sole treatment option [3,4,5]. The aggressiveness of this cancer and the scarcity of effective treatment options evidence the need of developing new therapeutic agents
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