Akademik Veri Yönetim Sistemi
Naunyn-Schmiedeberg's archives of pharmacology, 2024 (SCI-Expanded)
Accumulating evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may be effective at eliminating tumor cells. While empagliflozin exhibits nearly the highest selectivity for SGLT2 over SGLT1, its specific impact alone and in combination with tamoxifen remains largely unexplored in estrogen receptor alpha-positive (ER alpha +) breast cancer. This study investigated the anticancer effects of empagliflozin and its potential synergy with tamoxifen in MCF-7 breast cancer cells. The individual and combined cytotoxic effects of empagliflozin and tamoxifen were assessed using the xCELLigence system. The activities of AMP-activated protein kinase alpha (AMPK alpha), p38 mitogen-activated protein kinase (p38 MAPK alpha), p70-S6 kinase 1 (p70S6K1), and protein kinase B (Akt) were assessed using Western blotting. The gene expression levels of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) and Forkhead box O3a (FOXO3a) were assessed via qPCR. Our results revealed time- and concentration-dependent cytotoxic effects of empagliflozin and tamoxifen whether administered separately or in combination. While tamoxifen exhibits potency with an IC50 value of 17 mu M, approximately ten times greater than that of empagliflozin (IC50 = 177 mu M), synergistic effects are observed when the concentrations of the two agents approach their respective IC50 values. Additionally, empagliflozin significantly increases AMPK alpha activity while concurrently inhibiting Akt, p70S6K1, and p38 MAPK alpha, and these effects are significantly enhanced when empagliflozin is combined with tamoxifen. Moreover, empagliflozin modulates the gene expression, downregulating PGC-1 alpha while upregulating FOXO3a. Empagliflozin exerts anti-proliferative and anti-survival effects by inhibiting mTOR, Akt, and PGC-1 alpha, and it exhibits synergy with tamoxifen in MCF-7 breast cancer cells.Graphical AbstractProposed anticancer mechanism of empagliflozin in MCF-7 breast cancer cells.