Targeting cancer lactate metabolism with synergistic combinations of synthetic catalysts and monocarboxylate transporter inhibitors

IF 2.7 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY JBIC Journal of Biological Inorganic Chemistry Pub Date : 2023-03-08 DOI:10.1007/s00775-023-01994-3
Hannah E. Bridgewater, Elizabeth M. Bolitho, Isolda Romero-Canelón, Peter J. Sadler, James P. C. Coverdale
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Abstract

Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring. We show that the activity of the synthetic organometallic redox catalyst [Os(p-cymene)(TsDPEN)] (1), which can reduce pyruvate to un-natural d-lactate in MCF7 breast cancer cells using formate as a hydride source, is significantly increased in combination with the monocarboxylate transporter (MCT) inhibitor AZD3965. AZD3965, a drug currently in clinical trials, also significantly lowers the intracellular level of glutathione and increases mitochondrial metabolism. These synergistic mechanisms of reductive stress induced by 1, blockade of lactate efflux, and oxidative stress induced by AZD3965 provide a strategy for low-dose combination therapy with novel mechanisms of action.

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利用合成催化剂和单羧酸转运蛋白抑制剂协同组合靶向癌症乳酸代谢
合成抗癌催化剂为低剂量治疗和靶向生化途径提供了新的途径。例如,手性有机锇配合物可以催化丙酮酸的不对称转移氢化,丙酮酸是细胞中产生能量的关键底物。然而,小分子合成催化剂很容易中毒,因此需要在这种情况发生之前或避免这种情况发生之前优化其活性。我们发现,合成有机金属氧化还原催化剂[Os(p-cymene)(TsDPEN)](1)在MCF7乳腺癌细胞中以甲酸盐作为氢化物源,可以将丙酮酸还原为非天然d-乳酸,与单羧酸转运体(MCT)抑制剂AZD3965联合使用,活性显著提高。目前正在临床试验的药物AZD3965也能显著降低细胞内谷胱甘肽水平,增加线粒体代谢。1诱导的还原性应激、阻断乳酸外排和AZD3965诱导的氧化应激的协同机制为低剂量联合治疗提供了一种新的作用机制。图形抽象
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来源期刊
JBIC Journal of Biological Inorganic Chemistry
JBIC Journal of Biological Inorganic Chemistry 化学-生化与分子生物学
CiteScore
5.90
自引率
3.30%
发文量
49
审稿时长
3 months
期刊介绍: Biological inorganic chemistry is a growing field of science that embraces the principles of biology and inorganic chemistry and impacts other fields ranging from medicine to the environment. JBIC (Journal of Biological Inorganic Chemistry) seeks to promote this field internationally. The Journal is primarily concerned with advances in understanding the role of metal ions within a biological matrix—be it a protein, DNA/RNA, or a cell, as well as appropriate model studies. Manuscripts describing high-quality original research on the above topics in English are invited for submission to this Journal. The Journal publishes original articles, minireviews, and commentaries on debated issues.
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