Dehydroepiandrosterone-α-2-Deoxyglucoside Exhibits Enhanced Anticancer Effects in MCF-7 Breast Cancer Cells and Inhibits Glucose-6-Phosphate Dehydrogenase Activity

IF 3.2 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hsu-Feng Liu, Shen-Chieh Chou, Sheng-Cih Huang, Tzu-Yu Huang, Po-Yun Hsiao, Feng-Pai Chou, Tung-Kung Wu
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Abstract

In the pentose phosphate pathway, dehydroepiandrosterone (DHEA) uncompetitively inhibits glucose-6-phosphate dehydrogenase (G6PD), reducing NADPH production and increasing oxidative stress, which can influence the onset and/or progression of several diseases, including cancer. 2-Deoxy-D-glucose (2-DG), a glucose mimetic, competes with glucose for cellular uptake, inhibiting glycolysis and competing with glucose-6-phosphate (G-6-P) for G6PD activity. In this study, we report that DHEA-α-2-DG (5), an α-covalent conjugate of DHEA and 2-DG, exhibits better anticancer activity than DHEA, 2-DG, DHEA +2-DG, and polydatin in MCF-7 cells, and reduces NADPH/NADP+ ratio in cellular assays. In vitro enzyme kinetics and molecular docking studies showed that 5 uncompetitively inhibits human G6PD activity and binds to the structural NADP+ site but not to the catalytic NADP+ site. Further combining 5 with the FDA-approved drug tamoxifen enhanced its cytotoxicity against MCF-7 cells, suggesting that it could serve as a candidate for combination of drug strategies.

Abstract Image

脱氢表雄酮-α-2-脱氧葡萄糖苷可增强 MCF-7 乳腺癌细胞的抗癌效果并抑制葡萄糖-6-磷酸脱氢酶的活性
在磷酸戊糖途径中,脱氢表雄酮(DHEA)对葡萄糖-6-磷酸脱氢酶(G6PD)具有非竞争性抑制作用,从而减少了 NADPH 的产生,增加了氧化应激,这可能会影响包括癌症在内的多种疾病的发生和/或发展。2-脱氧-D-葡萄糖(2-DG)是一种葡萄糖模拟物,可与葡萄糖竞争细胞摄取,抑制糖酵解,并与葡萄糖-6-磷酸(G-6-P)竞争 G6PD 活性。在这项研究中,我们报告了 DHEA-α-2-DG (5)(一种 DHEA 和 2-DG 的 α 共价共轭物)在 MCF-7 细胞中表现出比 DHEA、2-DG、DHEA +2-DG 和多铂更好的抗癌活性,并在细胞测定中降低 NADPH/NADP+ 比率。体外酶动力学和分子对接研究表明,5 对人类 G6PD 的活性具有非竞争性抑制作用,能与结构性 NADP+ 位点结合,但不能与催化 NADP+ 位点结合。进一步将 5 与美国 FDA 批准的药物他莫昔芬联合使用,可增强其对 MCF-7 细胞的细胞毒性,这表明它可作为联合用药策略的候选药物。
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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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