The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters.
The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters.
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DOI：
10.1042/bj20151120
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Halestrap AP
中科院分区：
文献类型：
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作者：
Nancolas B;Guo L;Zhou R;Nath K;Nelson DS;Leeper DB;Blair IA;Glickson JD;Halestrap AP
Lonidamine （LND）是一种抗肿瘤药物，在选择性地使肿瘤对化疗、热疗和放疗敏感方面特别有效，尽管其确切的作用方式尚不清楚。据报道，它通过抑制糖酵解和线粒体呼吸来扰乱细胞的生物能量学，而间接证据表明，它也可能抑制由质子连接的单羧酸转运体（MCT）家族成员介导的细胞l -乳酸外排，以及线粒体丙酮酸载体（MPC）对线粒体丙酮酸的摄取。这里我们直接测试这些可能性。研究表明，LND能有效抑制离体大鼠肝脏线粒体（Ki 2.5 μM）的MPC活性，并协同抑制非洲爪蟾卵母细胞中表达的MCT1、MCT2和MCT4的l -乳酸转运，其K0.5和Hill系数分别为36-40 μM和1.65-1.85。在大鼠心脏线粒体中，LND对MPC具有相似的抑制作用，对丙酮酸解偶联氧化的抑制作用（IC50 ~7 μM）比谷氨酸等其他底物（IC50 ~20 μM）更有效。在分离的DB-1黑色素瘤细胞中，1-10 μM LND增加了l -乳酸输出，与MPC抑制一致，但较高浓度（150 μM）降低了l -乳酸输出，同时使细胞内[l -乳酸]>增加了5倍，与MCT抑制一致。我们得出结论，MPC抑制是LND最敏感的抗肿瘤靶点，对mct介导的l -乳酸外排和谷氨酰胺/谷氨酸氧化具有额外的抑制作用。这些作用可以解释LND对l -乳酸、细胞内pH （pHi）和ATP水平的选择性肿瘤效应，这些效应可以部分地被已建立的MPC和MCT抑制剂α-氰基-4-羟基肉桂酸模拟。
Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitising tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Here we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and cooperatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill Coefficient values of 36–40 μM and 1.65–1.85. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50 ~7 μM) than other substrates including glutamate (IC50 ~20 μM). In isolated DB-1 melanoma cells 1–10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output while increasing intracellular [L-lactate] > five-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate.