The phytochemical resveratrol, which is found in grapes and red wine, has been reported to have a variety of biological properties. It was shown in our previous research that introduction of additional hydroxyl groups into the stilbene structure increases the biological activity of resveratrol. In this study, the activity of 3,3',4,4',5,5'-hexahydroxystilbene (M8) was investigated in ZR-75-1, MDA-MB-231 and T47D human breast cancer cells. For evaluation of cytotoxic activity of M8, clonogenic and cell proliferation assays were used. The IC50 values obtained in the clonogenic assay were 0.846 microM for T47D, 8.53 microM for ZR-75-1 cells and 25.5 microM for MDA-MB-231, while IC50 values obtained in the cell proliferation assay were significantly higher: 90.1 microM, 98.4 microM, 127.8 microM for T47D, ZR-75-1 and MDA-MB-231 cells, respectively. Compound M8 caused the activation of caspase-8 in MDA-MB-231 cells (marker of extrinsic apoptotic pathway), while activities of caspase-9 (marker of intrinsic apoptotic pathway) and caspase-3 were increased in all 3 tested cell lines. Activation of caspase-9 and caspase-3 was connected with loss of mitochondrial potential and increase of p53, which could have an impact on downregulation of mitochondrial superoxide dismutase (MnSOD) seen in our experiments. MnSOD is a key enzyme providing antioxidative defense in mitochondria - the cellular center of reactive oxygen species' generation. Downregulation of MnSOD can therefore cause a significant decrease of antioxidant defense in cancer cells. An increase of oxidative stress conditions was suggested by loss of reduced glutathione in tested cells. Since cancer cells are usually under permanent oxidative stress, additional increased ROS generation as a result of the interaction of M8 with the mitochondrial respiratory chain and a decrease in oxidative defense can therefore be a promising method for selective elimination of cancer cells.

译文

据报道,在葡萄和红酒中发现的植物化学白藜芦醇具有多种生物学特性。在我们先前的研究中表明,在二苯乙烯结构中引入额外的羟基可以提高白藜芦醇的生物活性。在这项研究中,在ZR-75-1,MDA-MB-231和T47D人乳腺癌细胞中研究了3,3 ',4,4',5,5 '-六羟基二苯乙烯 (M8) 的活性。为了评估M8的细胞毒性活性,使用了克隆形成和细胞增殖测定法。在克隆形成测定中获得的IC50值为T47D的0.846微m、ZR-75-1细胞的8.53微m和MDA-MB-231的25.5微m,而在细胞增殖测定中获得的IC50值显著更高: 分别为T47D的90.1微m、98.4微m、127.8微m、ZR-75-1和MDA-MB-231细胞。化合物M8引起MDA-MB-231细胞中caspase-8的激活 (外源性凋亡途径的标记),而caspase-9 (内源性凋亡途径的标记) 和caspase-3的活性在所有3种测试细胞系中均增加。caspase-9和caspase-3的激活与线粒体潜能的丧失和p53的增加有关,这可能对我们实验中看到的线粒体超氧化物歧化酶 (MnSOD) 的下调产生影响。MnSOD是在线粒体中提供抗氧化防御的关键酶-活性氧物种产生的细胞中心。因此,MnSOD的下调会导致癌细胞中抗氧化防御的显着降低。测试细胞中还原型谷胱甘肽的丢失提示氧化应激条件增加。由于癌细胞通常处于永久性氧化应激状态,因此,由于M8与线粒体呼吸链的相互作用以及氧化防御能力的降低,额外增加的ROS生成可能是选择性消除癌细胞的有希望的方法。

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