Mechanism of antineoplastic activity of lonidamine.
Mechanism of antineoplastic activity of lonidamine.
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DOI：
10.1016/j.bbcan.2016.08.001
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发表时间：
2016-12
影响因子：
11.2
通讯作者：
Glickson, Jerry D.
中科院分区：
文献类型：
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作者：
Nath, Kavindra;Guo, Lili;Nancolas, Bethany;Nelson, David S.;Shestov, Alexander A.;Lee, Seung-Cheol;Roman, Jeffrey;Zhou, Rong;Leeper, Dennis B.;Halestrap, Andrew P.;Blair, Ian A.;Glickson, Jerry D.
关键词：
洛尼达胺(LND)最初是作为一种抗精子药引入的。后来发现它具有抗癌活性，使肿瘤对化疗、放射、光动力疗法和热疗敏感。虽然作用机制尚不清楚，但LND治疗已被认为是针对癌细胞的代谢途径。已有报道通过抑制糖酵解和线粒体呼吸来改变肿瘤细胞的生物能量学，而间接证据表明，它还抑制由质子连接的单羧酸转运体(MCT)家族成员介导的L乳酸外流，以及线粒体丙酮酸载体(MPC)对丙酮酸的摄取。最近的研究表明，低密度脂蛋白能有效地抑制大鼠肝脏线粒体MPC活性(Ki2.5μM)，并协同抑制非洲爪哇卵母细胞表达的MCT1、MCT2和MCT4对L乳酸的转运，其K0.5和希尔系数分别为36~40μM和1.65~1.85。在大鼠心肌中，LnD抑制作用相似，丙酮酸解偶联氧化的抑制作用(IC50~7μM)强于谷氨酸(IC50~20μM)。LND在不完全阻断琥珀酸脱氢酶活性的情况下抑制呼吸复合体II的琥珀酸-泛醌还原酶活性。LND还通过复合体II诱导细胞内的活性氧，据报道，LND通过抑制磷酸戊糖途径促进细胞死亡，从而抑制NADPH和谷胱甘肽的生成。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、复合体II和谷氨酰胺/谷氨酸氧化均有抑制作用。
Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited 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). Recent studies have demonstrated 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, respectively. 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). 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 and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. 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, Complex II and glutamine/glutamate oxidation.
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影响因子：
4.2
作者：
Cervantes-Madrid, Diana;Duenas-Gonzalez, Alfonso
通讯作者：
Duenas-Gonzalez, Alfonso
影响因子：
45.3
作者：
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Comella, G
影响因子：
3.9
作者：
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Ross, BD
影响因子：
6.4
作者：
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通讯作者：
SMETS, LA
影响因子：
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作者：
CONTU, A;OLMEO, NA;PAGA, C
通讯作者：
PAGA, C