Gallium(III)-2-benzoylpyridine-thiosemicarbazone complexes promote apoptosis through Ca2 signaling and ROS-mediated mitochondrial pathways
Gallium(III)-2-benzoylpyridine-thiosemicarbazone complexes promote apoptosis through Ca2 signaling and ROS-mediated mitochondrial pathways
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镓(III)-2-苯甲酰吡啶-缩氨基硫脲复合物通过 Ca2 信号传导和 ROS 介导的线粒体途径促进细胞凋亡
DOI：
10.1039/c8nj00697k
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发表时间：
2018
影响因子：
3.3
通讯作者：
Wang Yihong
中科院分区：
文献类型：
--
作者：
Qi Jinxu;Qian Kun;Tian Liang;Cheng Zhen;Wang Yihong
Ga（III）化合物是非常有希望的抗肿瘤药物。Ga（III）复合物处理后细胞内活性氧（ROS）水平显著升高，但这些复合物不具有氧化还原活性。为了研究Ga（III）配合物对ROS水平的影响，我们合成了三个双连接的镓(III) - 2-苯甲酰吡啶-硫代氨基脲配合物，并研究了它们的抗肿瘤机制。用x射线单晶衍射对Ga（III）配合物的结构进行了鉴定。细胞毒性分析表明，与正常细胞相比，配体和镓复合物具有较高的抗肿瘤活性和较低的细胞毒性。其中最活跃的络合物是C3，其抗肿瘤活性优于其相关配体和抗癌剂3-AP。因此，Ga（III）复合物不仅传递铁离子，而且诱导细胞内Ca2+释放。结果，氧化还原活性铁配合物中的ROS标准升高。其机制涉及缺乏膜电位的线粒体释放Cyt C，然后激活caspase家族蛋白刺激细胞凋亡。
Ga(III) compounds are highly promising candidates for antitumor therapy. The level of intracellular reactive oxygen species (ROS) is significantly increased after Ga(III) complex treatment, but these complexes are redox-inactive. To investigate the effects of Ga(III) complexes on ROS levels, we synthesized three bis-ligated gallium(III)–2-benzoylpyridine-thiosemicarbazone complexes and studied their antitumor mechanisms. The structures of the Ga(III) complexes were identified by X-ray single-crystal diffraction. Cytotoxicity analysis demonstrated that the ligands and gallium complexes exerted a higher antitumor activity and a lower cytotoxicity than those of normal cells. The most active complex was C3, which exhibited a better antitumor viability than its related ligands and the anticancer agent 3-AP. Thus, the Ga(III) complexes not only transmitted the iron ions but also induced intracellular Ca2+ release. As a result, the ROS standards in redox-active iron complexes were increased. The mechanism involved the release of Cyt C from the mitochondria which lack membrane potential, and then the activation of the caspase family proteins stimulated cell apoptosis.