EGCG-Derivative G28 Shows High Efficacy Inhibiting the Mammosphere-Forming Capacity of Sensitive and Resistant TNBC Models

Abstract

Recent studies showed that Fatty Acid Synthase (FASN), a lipogenic enzyme overexpressed in several carcinomas, plays an important role in drug resistance. Furthermore, the enrichment of Breast Cancer Stem Cell (BCSC) features has been found in breast tumors that progressed after chemotherapy. Hence, we used the triple negative breast cancer (TNBC) cell line MDA-MB-231 (231) to evaluate the FASN and BCSC population role in resistance acquisition to chemotherapy. For this reason, parental cell line (231) and its derivatives resistant to doxorubicin (231DXR) and paclitaxel (231PTR) were used. The Mammosphere-Forming Assay and aldehyde dehydrogenase (ALDH) enzyme activity assay showed an increase in BCSCs in the doxorubicin-resistant model. Moreover, the expression of some transcription factors involved in epithelial-mesenchymal transition (EMT), a process that confers BCSC characteristics, was upregulated after chemotherapy treatment. FASN inhibitors C75, (−)-Epigallocatechin 3-gallate (EGCG), and its synthetic derivatives G28, G56 and G37 were used to evaluate the effect of FASN inhibition on the BCSC-enriched population in our cell lines. G28 showed a noticeable antiproliferative effect in adherent conditions and, interestingly, a high mammosphere-forming inhibition capacity in all cell models. Our preliminary results highlight the importance of studying FASN inhibitors for the treatment of TNBC patients, especially those who progress after chemotherapy.

The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis

“…Overexpression of FFAs confers many advantages to tumor cells, such as BC cells. It also plays a critical role in chemoresistance acquisition ( 9 , 10 ). Therefore, it is important to further understand the relationship between FFA synthesis and DOX resistance, which may help improve clinical employment of the drug.…”

Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment

“…In a mouse MDAMB-468 xenograft tumor model, co-administration of 2-DG plus gefitinib significantly reduced tumor size. G28, a fatty acid synthase (FASN) inhibitor, had a substantial antiproliferative effect on the TNBC cell line MDA-MB-231) and its doxorubicin (231DXR) and paclitaxel-resistant variants (231PTR) [ 61 ]. EGCG, an anti-FASN compound, in combination with cetuximab, showed potent anticancer efficacy in doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) [ 62 ].…”

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

“…EGCG was purchased from Sigma (USA) and G28 was synthesized as described elsewhere [43]. For monotreatment assays, after 24 h cells were treated with different concentrations of each drug for 72 h. Cell viability was determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay (Sigma) as described elsewhere [44]. For drug combination experiments, cells were treated with three fixed concentrations of gefitinib (1, 2.5, and 5 µM) or osimertinib (0.5, 1, and 2 µM) in combination of a series of increasing concentrations of EGCG or G28 for 72 h. Following treatment, cell proliferation was measured using the standard colorimetric MTT assay.…”

“…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].…”