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首页> 外文期刊>Molecular cancer therapeutics >Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria.
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Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria.

机译：通过直接靶向线粒体，Flex-Hets在正常细胞上差异诱导癌症的凋亡。

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Flex-Het drugs induce apoptosis in multiple types of cancer cells, with little effect on normal cells. This apoptosis occurs through the intrinsic mitochondrial pathway accompanied by generation of reactive oxygen species (ROS). The objective of this study was to determine if direct or indirect targeting of mitochondria is responsible for the differential sensitivities of cancer and normal cells to Flex-Hets. Mitochondrial effects and apoptosis were measured using JC-1 and Annexin V-FITC dyes with flow cytometry. Bcl-2, Bcl-x(L), and Bax were measured by Western blot. Flex-Hets induced mitochondrial swelling and apoptosis in ovarian cancer cell lines but had minimal to no effects in a variety of normal cell cultures, including human ovarian surface epithelium. Effects on inner mitochondrial membrane (IMM) potential were variable and did not occur in normal cells. Two different antioxidants, administered at concentrations shown to quench intracellular and mitochondrial ROS, did not alter Flex-Het-induced mitochondrial swelling, loss of IMM potential, or apoptosis. Inhibition of protein synthesis with cycloheximide also did not prevent Flex-Het mitochondrial or apoptosis effects. Bcl-2 and Bcl-x(L) levels were decreased in an ovarian cancer cell line but increased in a normal culture, whereas Bax expression was unaffected by Flex-Hets treatment. In conclusion, ROS seems to be a consequence rather than a cause of mitochondrial swelling. The differential induction of apoptosis in cancer versus normal cells by Flex-Hets involves direct targeting of mitochondria associated with alterations in the balance of Bcl-2 proteins. This mechanism does not require IMM potential, ROS generation, or protein synthesis.
机译：Flex-Het药物可诱导多种类型癌细胞的凋亡，而对正常细胞的影响很小。这种凋亡通过固有的线粒体途径发生，并伴随着活性氧（ROS）的产生。这项研究的目的是确定直接或间接靶向线粒体是造成癌症和正常细胞对Flex-Hets敏感性差异的原因。使用JC-1和膜联蛋白V-FITC染料通过流式细胞仪检测线粒体效应和细胞凋亡。通过蛋白质印迹法测量Bcl-2，Bcl-x（L）和Bax。 Flex-Hets在卵巢癌细胞系中诱导线粒体肿胀和凋亡，但在包括人卵巢表面上皮在内的多种正常细胞培养物中几乎没有影响。对内线粒体膜（IMM）电位的影响是可变的，在正常细胞中不会发生。两种不同的抗氧化剂，以显示出淬灭细胞内和线粒体ROS的浓度给药，不会改变Flex-Het诱导的线粒体肿胀，IMM电位丧失或凋亡。用环己酰亚胺抑制蛋白质合成也不能阻止Flex-Het线粒体或细胞凋亡作用。 Bcl-2和Bcl-x（L）水平在卵巢癌细胞系中降低，但在正常培养中升高，而Bax表达不受Flex-Hets处理的影响。总之，ROS似乎是线粒体肿胀的结果而不是原因。 Flex-Hets对癌症细胞与正常细胞的凋亡诱导差异涉及直接靶向线粒体，该线粒体与Bcl-2蛋白平衡的改变有关。该机制不需要IMM电位，ROS生成或蛋白质合成。

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