Mitochondrial permeability transition as target of anticancer drugs.
Mitochondrial permeability transition as target of anticancer drugs.
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DOI：
10.2174/13816128113199990033
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发表时间：
2014
影响因子：
3.1
通讯作者：
L. Dalla Via;A. García-Argáez;M. Martínez-Vázquez;S. Grancara;P. Martinis;A. Toninello
中科院分区：
文献类型：
--
作者：
L. Dalla Via;A. García-Argáez;M. Martínez-Vázquez;S. Grancara;P. Martinis;A. Toninello
线粒体是细胞的能量源，但也包含导致细胞死亡的机制。许多信号聚集在线粒体上，通过线粒体通透性过渡（MPT）诱导和过渡孔（PTPs）的打开，引起线粒体膜的通透性。这些事件导致离子稳态丧失，基质肿胀，外膜破裂导致促凋亡因子释放，以及生物能量功能的损害。MPT诱导的分子机制尚未完全阐明，然而，越来越多的证据支持这一概念，即肿瘤细胞线粒体中药理诱导ppt是一种有效且有希望的治疗癌症的策略。本文的第一部分综述了PTP的主要成分和几种针对PTP的化合物诱导PTP现象的研究进展。文章的第二部分介绍了近年来该领域的实验进展，特别是从桃金娘根中分离的甾醇（PEN）在细胞和线粒体水平上的作用。PEN对一些人类肿瘤细胞系显示出细胞毒性活性，其机制可归因于位于腺嘌呤核苷酸转位酶（PTP主要参与的蛋白质）上的关键硫醇的氧化。这一事件在Ca（2+）存在下诱导MPT，并释放促凋亡因子细胞色素c和凋亡诱导因子。这些观察结果表明，PEN可能触发caspase依赖性和caspase非依赖性凋亡途径。这一特性使PEN成为一种非常有趣的化合物，可以开发出更有效的靶向线粒体的抗增殖药物来进行抗癌治疗。
Mitochondria are the cell powerhouses but also contain the mechanisms leading to cell death. Many signals converge on mitochondria to cause the permeabilization of mitochondrial membranes by the mitochondrial permeability transition (MPT) induction and the opening of transition pores (PTPs). These events cause loss of ionic homeostasis, matrix swelling, outer membrane rupture leading to pro-apoptotic factors release, and impairment of bioenergetics functions. The molecular mechanism underlying MPT induction is not completely elucidated however, a growing body of evidence supports the concept that pharmacological induction of PTPs in mitochondria of neoplastic cells is an effective and promising strategy for therapeutic approaches against cancer. The first part of this article presented as a review also evidences the main constituents of PTP and several compounds targeting them for inducing the phenomenon. The second part of the article regards the recent experimental development in the field, in particular, the effects of peniocerol (PEN), a sterol isolated from the root of Myrtillocactus geometrizans, at cellular and mitochondrial level. PEN exhibits a cytotoxic activity on some human tumor cell lines, whose mechanism is attributable to the oxidation of critical thiols located on adenine nucleotide translocase, the protein mainly involved in PTP. This event in the presence of Ca(2+) induces the MPT with the release of the pro-apoptotic factors cytochrome c and apoptosis inducing factor. These observations evidence that PEN may trigger both the caspase-dependent and caspaseindependent apoptotic pathways. This characteristic renders PEN a very interesting compound that could be developed to obtain more effective antiproliferative agents targeting mitochondria for anticancer therapy.