Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death.
Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death.
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DOI：
10.1186/1471-2407-13-285
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发表时间：
2013-06-13
期刊：
影响因子：
3.8
通讯作者：
Kalyanaraman B
中科院分区：
文献类型：
--
作者：
Cheng G;Zielonka J;McAllister DM;Mackinnon AC Jr;Joseph J;Dwinell MB;Kalyanaraman B
最近的研究表明，针对线粒体生物能代谢是一种有前途的化疗策略。成功实施这种化疗策略的关键是使用新型和改进的线粒体靶向阳离子药物，选择性抑制乳腺癌细胞的能量代谢，同时对正常细胞产生很少或没有长期细胞毒性作用。在这项研究中，我们研究了线粒体靶向维生素 E 类似物 (Mito-chromanol、Mito-ChM) 及其乙酰化酯类似物 (Mito-ChMAc) 诱导的细胞毒性和生物能代谢变化。对细胞死亡、集落形成、线粒体生物能功能、细胞内 ATP 水平、测试化合物的细胞内和组织浓度以及体内肿瘤生长进行了测定。 Mito-ChM 和 Mito-ChMAc 都选择性地消耗细胞内 ATP，并导致乳腺癌细胞中 ATP 相关耗氧率的长期抑制，但在非癌细胞中则不然。糖酵解的抑制显着增强了这些作用。 Mito-ChM 和 Mito-ChMAc 在几种不同遗传背景的乳腺癌细胞中表现出抗增殖作用和细胞毒性。此外，Mito-ChM 在人类乳腺癌异种移植模型中选择性积累在肿瘤组织中并抑制肿瘤生长。我们的结论是，靶向线粒体的小分子量苯并二氢吡喃醇在多种乳腺癌细胞中表现出选择性的抗增殖作用和细胞毒性，并且线粒体苯并二氢苯并二氢吡喃醇中羟基的酯化并不是其抗增殖和细胞毒性作用的关键要求。
Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells. In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed. Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer. We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect.
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影响因子：
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