The elusiveness of triple-negative breast cancer from targeted therapy has redirected focus toward exploiting the metabolic shortcomings of these highly metastatic subtypes of breast cancer. Cueing from the metabolic heterogeneity of TNBC and the exposition of the dual dependence of some TNBCs on OXPHOS and glycolysis for ATP, we herein report the efficacy of cotreatment of TNBCs with an OXPHOS inhibitor, 2a and 2DG, a potent glycolysis inhibitor. 2a-2DG cotreatment inhibited TNBC cell proliferation with IC50 of ∼5 to 36 times lower than that of 2a alone and over 5000 times lower than IC50 of 2DG alone. 2a-2DG cotreatment suppressed mitochondrial ATP production and significantly induced AMPK activation. Mechanistic studies revealed the distinct yet synergistic contributions of 2a and 2DG to the antiproliferative effect of the cotreatment. While 2a induced apoptotic cell death, 2DG sensitized TNBCs to the antiproliferative effects of 2avia endoplasmic reticulum stress induction. Strikingly, the combination of 2a-2DG ablated SUM159 tumors in an orthotopic xenograft mouse model. This study highlights the synergistic effect of a gold-based complex with 2DG and the potential benefit of multimetabolic pathways targeting as an effective therapeutic strategy against TNBCs.

中文翻译：

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金 （III） 二硫代氨基甲酸酯和 2-脱氧葡萄糖诱导的能量和内质网应激协同触发乳腺癌细胞死亡


靶向治疗对三阴性乳腺癌的难以捉摸性已将重点转向利用这些高度转移性乳腺癌亚型的代谢缺陷。从 TNBC 的代谢异质性以及一些 TNBC 对 OXPHOS 和 ATP 糖酵解的双重依赖性来看，我们在此报道了 TNBC 与 OXPHOS 抑制剂 2a 和 2DG（一种有效的糖酵解抑制剂）共同治疗的疗效。2a-2DG 共处理抑制 TNBC 细胞增殖，IC50 比单独使用 2a 低 ∼ 5 至 36 倍，比单独使用 2DG 的 IC50 低 5000 倍以上。2a-2DG 共处理抑制线粒体 ATP 产生并显着诱导 AMPK 激活。机制研究揭示了 2a 和 2DG 对共处理的抗增殖作用的独特但协同作用。虽然 2a 诱导凋亡细胞死亡，但 2DG 使 TNBC 对 2avia 内质网应激诱导的抗增殖作用敏感。引人注目的是，2a-2DG 的组合在原位异种移植小鼠模型中消融了 SUM159 肿瘤。本研究强调了金基复合物与 2DG 的协同作用，以及靶向多代谢途径作为针对 TNBC 的有效治疗策略的潜在益处。