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硫氧还蛋白还原酶(TrxR)是哺乳动物细胞内负责清除过量活性氧族(ROS)的重要酶类。本研究的目的是探究ROS在TrxR抑制剂乙烷硒啉抗肿瘤机制中的作用。在人肺癌细胞A549中,乙烷硒啉迅速诱导ROS含量上升和线粒体膜电位下降,并导致细胞死亡。ROS清除剂N-乙酰半胱氨酸的预孵育可以显著抵抗这三种现象。AnnexinV-PI法和Western blot的结果表明乙烷硒啉激活了内源性凋亡通路。线粒体通透性转变孔道抑制剂环孢菌素A可以抑制乙烷硒啉诱发的细胞色素c释放和细胞死亡,而同时一些Bcl-2家族蛋白含量却没有明显变化。这些结果说明ROS可能部分地通过增加线粒体通透性,释放包括线粒体内的促凋亡因子来介导乙烷硒啉诱发的快速凋亡。首次报道了ROS可能在乙烷硒啉抗肿瘤机制,特别是其早期过程中有重要作用。
Thioredoxin reductase (TrxR) is an important enzyme in mammalian cells responsible for the removal of excess reactive oxygen species (ROS). The purpose of this study was to explore the role of ROS in the antitumor mechanism of ethaselen, a TrxR inhibitor. In human lung cancer A549 cells, ethaneselen rapidly induced an increase in ROS content and decreased mitochondrial membrane potential and resulted in cell death. Pre-incubation of ROS scavenger N-acetylcysteine can significantly counteract these three phenomena. AnnexinV-PI and Western blot results show that ethaselenol activates the endogenous apoptotic pathway. Cytosporin A, an inhibitor of mitochondrial permeability transition, inhibits ethaneselen-induced cytochrome c release and cell death, while some Bcl-2 family proteins do not change significantly. These results indicate that ROS may mediate ethaselen-induced rapid apoptosis, in part, by increasing mitochondrial permeability and releasing mitochondrial pro-apoptotic factors. It was first reported that ROS may play an important role in the anti-tumor mechanism of ethaselen, especially in its early stage.