Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.
Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.
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DOI：
10.1074/jbc.m115.697516
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发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
Blair IA
中科院分区：
文献类型：
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作者：
Guo L;Shestov AA;Worth AJ;Nath K;Nelson DS;Leeper DB;Glickson JD;Blair IA
抗肿瘤药物lonidamine （LND; 1-（2,4-二氯苯基）- 1h -吲唑-3-羧酸）已知会干扰癌细胞的能量生成过程。然而，LND对中枢能量代谢的影响尚未得到充分表征。在这项研究中，我们报告了大量的琥珀酸盐在lnd处理的细胞中积累。LND抑制富马酸盐和苹果酸盐的形成，抑制琥珀酸盐诱导的分离线粒体呼吸。利用生化分析，我们确定LND抑制呼吸复合体II的琥珀酸-泛醌还原酶活性，而不完全阻断琥珀酸脱氢酶活性。LND还通过复合物II诱导细胞活性氧，从而降低DB-1黑色素瘤细胞系的活力。LND促进细胞死亡的能力通过抑制戊糖磷酸途径而增强，从而抑制NADPH和谷胱甘肽的产生。利用稳定同位素示踪剂结合同位素分析，我们发现LND增加了谷氨酰胺水解，但减少了谷氨酰胺衍生的α-酮戊二酸的还原羧化。我们对LND先前未被描述的作用的发现可能为靶向癌症代谢提供潜在的联合治疗方法。
The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism.