MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy.
MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy.
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DOI：
10.1158/0008-5472.can-16-2686
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发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Leach MO
中科院分区：
文献类型：
--
作者：
Beloueche-Babari M;Wantuch S;Casals Galobart T;Koniordou M;Parkes HG;Arunan V;Chung YL;Eykyn TR;Smith PD;Leach MO
单羧酸转运蛋白（MCT）调节肿瘤细胞代谢，为肿瘤治疗提供了有前途的治疗靶点。了解MCT阻断对肿瘤细胞代谢的影响可能有助于开发联合策略或确定药效学生物标志物，以支持目前正在临床试验中的MCT抑制剂的临床开发。在这项研究中，我们评估了MCT1抑制剂AZD 3965在体外和体内对癌细胞代谢的影响。将人淋巴瘤和结肠癌细胞暴露于AZD 3965增加了细胞内乳酸盐的MCT 4依赖性蓄积，抑制了单羧酸盐的流入和流出。AZD 3965还增加了TCA循环相关代谢物和13 C-葡萄糖线粒体代谢的水平，增强了氧化型丙酮酸脱氢酶和回补型丙酮酸羧化酶通量。线粒体代谢的增加是维持细胞在药物胁迫下存活所必需的。这些作用被线粒体复合物I抑制剂二甲双胍和线粒体丙酮酸载体抑制剂UK5099联合给药抵消。在人淋巴瘤小鼠异种移植模型中，AZD 3965给药后证实了体内生物能量学的改善。我们的研究结果揭示了可能用于治疗和药效学目的的MCT 1抑制的新的代谢后果。
Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle-related metabolites and 13C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by co-administration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing with AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes.