Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy
Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy
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DOI：
10.1016/j.freeradbiomed.2011.02.032
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发表时间：
2011-06-01
影响因子：
7.4
通讯作者：
Neuzil, Jiri
中科院分区：
文献类型：
--
作者：
Dong, Lan-Feng;Jameson, Victoria J. A.;Neuzil, Jiri
线粒体正在成为抗癌药物耐人寻味的靶点。我们在这里测试了一种新的方法，通过添加三苯基膦(TPP+)来增强抗癌药物的线粒体靶向递送。一种线粒体靶向的维生素E琥珀酸酯类似物(MitoVES)，通过用TPP+标记亲本化合物进行修饰，诱导了更强劲的癌细胞凋亡，与未修饰的类似物相比，抗癌活性增加了1-2个对数，同时保持了对恶性肿瘤细胞的选择性。这是因为MitoVES与线粒体结合，导致快速产生活性氧物种，进而触发线粒体依赖的细胞凋亡，涉及到对Bcl-2家族蛋白的转录调控。事实证明，与非靶向类似物相比，MitoVES在抑制实验性肿瘤方面更具优势。我们认为，线粒体靶向递送抗癌药物为提高具有抗癌活性的化合物的疗效提供了一种新的范式。(C)2011 Elsevier Inc.保留所有权利。
Mitochondria are emerging as intriguing targets for anti-cancer agents. We tested here a novel approach, whereby the mitochondrially targeted delivery of anti-cancer drugs is enhanced by the addition of a triphenylphosphonium group (TPP+). A mitochondrially targeted analog of vitamin E succinate (MitoVES), modified by tagging the parental compound with TPP+, induced considerably more robust apoptosis in cancer cells with a 1-2 log gain in anti-cancer activity compared to the unmodified counterpart, while maintaining selectivity for malignant cells. This is because MitoVES associates with mitochondria and causes fast generation of reactive oxygen species that then trigger mitochondria-dependent apoptosis, involving transcriptional modulation of the Bcl-2 family proteins. MitoVES proved superior in suppression of experimental tumors compared to the untargeted analog. We propose that mitochondrially targeted delivery of anti-cancer agents offers a new paradigm for increasing the efficacy of compounds with anti-cancer activity. (C) 2011 Elsevier Inc. All rights reserved.