Ruthenium(II) salicylate complexes inducing ROS-mediated apoptosis by targeting thioredoxin reductase
Ruthenium(II) salicylate complexes inducing ROS-mediated apoptosis by targeting thioredoxin reductase
复制标题
水杨酸钌 (II) 复合物通过靶向硫氧还蛋白还原酶诱导 ROS 介导的细胞凋亡
DOI：
10.1016/j.jinorgbio.2019.01.011
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发表时间：
2019-04-01
影响因子：
3.9
通讯作者：
Chen, Lan-mei
中科院分区：
文献类型：
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作者：
Chen, Jin-can;Zhang, Yao;Chen, Lan-mei
硫氧还蛋白还原酶（TrxR）是硫氧还蛋白系统的主要组成部分，在调节细胞氧化还原信号中起关键作用，并且被发现在许多人类癌细胞中过表达。TrxR已成为抗癌剂的有吸引力的靶标。本文合成并表征了三个水杨酸配体的钌配合物[Ru（phen）（2）（SA）]（phen = 1，10-菲咯啉，SA =水杨酸盐，1），[Ru（dmb）（2）（SA）]（dmb = 4，4 '-二甲基-2，2'-联吡啶，2）和[Ru（bpy）（2）（SA）]（bpy = 2，2 '-联吡啶，3）。评价了它们的抗癌作用。与顺铂相比，发现配合物1对癌细胞系显示出明显的抗癌活性，同时对正常细胞系BEAS-2B显示出低毒性。在A549细胞中研究了复合物1抑制癌细胞生长的机制。配合物1通过诱导细胞凋亡和将细胞周期阻滞在G 0/G1期发挥抗癌作用。复合物1可以选择性地抑制TrxR活性，从而促进活性氧（ROS）的产生和积累，其随后触发线粒体功能障碍和DNA损伤，激活氧化应激敏感的丝裂原活化蛋白激酶（MAPK），并抑制蛋白激酶13（PKB或AKT）信号通路，导致A549细胞凋亡。
Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. TrxR has become an attractive target for anticancer agents. In this work, three Ru(II) complexes with salicylate as ligand, [Ru (phen)(2)(SA)] (phen = 1,10-phenanthroline, SA = salicylate, 1), [Ru(dmb)(2)(SA)] (dmb = 4,4'-dimethyl-2,2'-bipyridine, 2) and [Ru(bpy)(2)(SA)] (bpy = 2,2'-bipyridine, 3), were synthesized and characterized. The anticancer effect exerted by them was evaluated. Complex 1 was found to exhibit obvious anticancer activity, in comparison with cisplatin, against cancer cell lines, while displaying low toxicity to the normal cell line BEAS-2B. The mechanism of complex 1 cancer cell growth suppress was investigated in A549 cells. Complex 1 exerted its anticancer through inducing apoptosis and triggering cell cycle arrest at the G0/G1 phase. Complex 1 can selectively inhibit TrxR activity and thus promote the generation and accumulation of reactive oxygen species (ROS), which subsequently trigger mitochondrial dysfunction and DNA damage, activate oxidative stress-sensitive mitogen activated protein kinase (MAPK), and suppress the protein kinase 13 (PKB or AKT) signal pathway, resulting in apoptosis in A549 cells.