Empagliflozin 在 ER 阳性乳腺癌细胞中显示出细胞毒性以及与他莫昔芬的协同作用:抗增殖和抗存活效应

Ahmad Karzoon, Mükerrem Betül Yerer, Ahmet Cumaoğlu
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引用次数: 0

摘要

越来越多的证据表明,钠-葡萄糖共转运体 2(SGLT2)抑制剂可有效清除肿瘤细胞。虽然与 SGLT1 相比,empagliflozin 对 SGLT2 的选择性几乎是最高的,但其单独或与他莫昔芬联用对雌激素受体 α 阳性(ERα +)乳腺癌的具体影响在很大程度上仍未得到探讨。本研究探讨了empagliflozin的抗癌作用及其与他莫昔芬在MCF-7乳腺癌细胞中的潜在协同作用。研究使用xCELLigence系统评估了安帕格列净和他莫昔芬的单独和联合细胞毒性作用。采用Western印迹法评估了AMP激活蛋白激酶α(AMPKα)、p38丝裂原活化蛋白激酶(p38 MAPKα)、p70-S6激酶1(p70S6K1)和蛋白激酶B(Akt)的活性。通过 qPCR 评估了过氧化物酶体增殖激活受体-γ 辅激活剂-1α(PGC-1α)和叉头盒 O3a(FOXO3a)的基因表达水平。我们的研究结果表明,无论是单独给药还是联合给药,安帕格列净和他莫昔芬都具有时间和浓度依赖性的细胞毒性作用。他莫昔芬的 IC50 值为 17 μM,大约是安帕格列嗪(IC50 = 177 μM)的十倍,而当两种药物的浓度接近各自的 IC50 值时,就会产生协同效应。此外,empagliflozin 能显著提高 AMPKα 的活性,同时抑制 Akt、p70S6K1 和 p38 MAPKα。此外,恩格列净还能调节基因表达,下调PGC-1α,上调FOXO3a。Empagliflozin通过抑制mTOR、Akt和PGC-1α发挥抗增殖和抗存活作用,它与他莫昔芬在MCF-7乳腺癌细胞中表现出协同作用。图解摘要Empagliflozin在MCF-7乳腺癌细胞中的抗癌机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Empagliflozin demonstrates cytotoxicity and synergy with tamoxifen in ER-positive breast cancer cells: anti-proliferative and anti-survival effects

Empagliflozin demonstrates cytotoxicity and synergy with tamoxifen in ER-positive breast cancer cells: anti-proliferative and anti-survival effects

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 α-positive (ERα +) 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 α (AMPKα), p38 mitogen-activated protein kinase (p38 MAPKα), 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-1α (PGC-1α) 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 μM, approximately ten times greater than that of empagliflozin (IC50 = 177 μM), synergistic effects are observed when the concentrations of the two agents approach their respective IC50 values. Additionally, empagliflozin significantly increases AMPKα activity while concurrently inhibiting Akt, p70S6K1, and p38 MAPKα, and these effects are significantly enhanced when empagliflozin is combined with tamoxifen. Moreover, empagliflozin modulates the gene expression, downregulating PGC-1α while upregulating FOXO3a. Empagliflozin exerts anti-proliferative and anti-survival effects by inhibiting mTOR, Akt, and PGC-1α, and it exhibits synergy with tamoxifen in MCF-7 breast cancer cells.

Graphical Abstract

Proposed anticancer mechanism of empagliflozin in MCF-7 breast cancer cells.

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