Hematology Division, Department of Internal Medicine, National Institute of Science and Technology on Cell Based Therapy, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Leukemia. 2012 Mar;26(3):451-60. doi: 10.1038/leu.2011.216. Epub 2011 Aug 26.
The vitamin E derivative (+)α-tocopheryl succinate (α-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARα transgenic mice, we demonstrated that α-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that α-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, α-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for α-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.
维生素 E 衍生物 (+)α-生育酚琥珀酸酯（α-TOS）在广泛的肿瘤中发挥促凋亡作用，并且对正常组织具有良好的耐受性。先前的研究表明线粒体参与了其作用机制；然而，其早期步骤尚未完全阐明。在源自 hCG-PML-RARα 转基因小鼠的急性早幼粒细胞白血病（APL）模型中，我们证明 α-TOS 与三氧化二砷或全反式维甲酸一样有效，这两种药物是目前的治疗金标准。我们还证明 α-TOS 诱导 APL 细胞中线粒体膜电位的早期耗散，并且使用分离的线粒体进行的研究表明，这种作用可能是由于抑制线粒体呼吸链复合物 I 所致。此外，α-TOS 在线粒体细胞色素 c 释放和半胱天冬酶激活之前数小时就促进了活性氧物质的积累。因此，α-TOS 揭示了体内抗白血病作用和新的线粒体靶点，同时线粒体呼吸复合物 I 被强调为潜在的抗癌治疗靶点。
