Inhibition of Mitochondrial Respiration and Rapid Depletion of Mitochondrial Glutathione by β-Phenethyl Isothiocyanate: Mechanisms for Anti-Leukemia Activity
Inhibition of Mitochondrial Respiration and Rapid Depletion of Mitochondrial Glutathione by β-Phenethyl Isothiocyanate: Mechanisms for Anti-Leukemia Activity
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DOI：
10.1089/ars.2011.4170
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发表时间：
2011-12-01
影响因子：
6.6
通讯作者：
Huang, Peng
中科院分区：
文献类型：
--
作者：
Chen, Gang;Chen, Zhao;Huang, Peng
目的：β-异硫氰酸苯乙酯（PEITC）是一种天然产物，对人白血病细胞（包括来自患者的耐药原代白血病细胞）具有有效的抗癌活性。本研究旨在研究PEITC有效抗白血病活性的关键机制，并评估其治疗潜力。结果如下：我们的研究表明，PEITC引起线粒体谷胱甘肽（GSH）的快速耗尽和活性氧（ROS）和一氧化氮的显着升高，并诱导线粒体电子传递复合物I的破坏表现为早期降解的NADH脱氢酶Fe-S蛋白-3和线粒体呼吸的显着抑制。使用生物化学和药理学方法，我们进一步表明，鱼藤酮单独抑制线粒体呼吸在白血病细胞中仅引起中度细胞毒性，而呼吸抑制和ROS生成剂的组合对白血病和淋巴瘤细胞表现出协同作用。创新与结论：虽然PEITC是一种反应性化合物，可能有多种作用机制，但我们发现GSH的快速消耗和线粒体呼吸的抑制是诱导白血病细胞协同细胞毒性的两个重要早期事件。这些发现不仅表明PEITC是一种有前途的化合物，可用于白血病治疗，而且还为开发新的治疗策略提供了基础，通过使用新的组合来调节ROS并抑制线粒体呼吸，从而有效地杀死白血病细胞。抗氧化剂。氧化还原信号。15，2911-2921.
Aims: beta-Phenethyl isothiocyanate (PEITC) is a natural product with potent anticancer activity against human leukemia cells including drug-resistant primary leukemia cells from patients. This study aimed at investigating the key mechanisms that contribute to the potent anti-leukemia activity of PEITC and at evaluating its therapeutic potential. Results: Our study showed that PEITC caused a rapid depletion of mitochondrial glutathione (GSH) and a significant elevation of reactive oxygen species (ROS) and nitric oxide, and induced a disruption of the mitochondrial electron transport complex I manifested by an early degradation of NADH dehydrogenase Fe-S protein-3 and a significant suppression of mitochondrial respiration. Using biochemical and pharmacological approaches, we further showed that inhibition of mitochondrial respiration alone by rotenone caused only a moderate cytotoxicity in leukemia cells, whereas a combination of respiratory inhibition and an ROS-generating agent exhibited a synergistic effect against leukemia and lymphoma cells. Innovation and Conclusion: Although PEITC is a reactive compound and might have multiple mechanisms of action, we showed that a rapid depletion of GSH and inhibition of mitochondrial respiration are two important early events that induced synergistic cytotoxicity in leukemia cells. These findings not only suggest that PEITC is a promising compound for potential use in leukemia treatment, but also provide a basis for developing new therapeutic strategies to effectively kill leukemia cells by using a novel combination to modulate ROS and inhibit mitochondrial respiration. Antioxid. Redox Signal. 15, 2911-2921.