Mitochondria-targeted platinum(II) complexes induce apoptosis-dependent autophagic cell death mediated by ER-stress in A549 cancer cells
Mitochondria-targeted platinum(II) complexes induce apoptosis-dependent autophagic cell death mediated by ER-stress in A549 cancer cells
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线粒体靶向铂 (II) 复合物诱导 A549 癌细胞中内质网应激介导的凋亡依赖性自噬细胞死亡
DOI：
10.1016/j.ejmech.2018.06.018
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发表时间：
2018
影响因子：
6.7
通讯作者：
Liang Hong
中科院分区：
文献类型：
--
作者：
Wang Feng-Yang;Tang Xiao-Ming;Wang Xia;Huang Ke-Bin;Feng Hai-Wen;Chen Zhen-Feng;Liu You-Nian;Liang Hong
具有多种肿瘤细胞死亡模式的药物可以成为有效的化疗药物。双模式化疗方法的一个例子是一种可以诱导细胞凋亡和自噬性死亡的药物。迄今为止，还没有临床抗癌药物被证明可以同时诱导这两种途径。单功能铂络合物是有效的抗癌候选药物，其作用机制与顺铂不同。在这里，我们描述了两种含有 8-取代喹啉衍生物作为配体的单官能铂配合物的合成和表征，[PtL1Cl]Cl [L1= (Z)-1-(吡啶-2-基)-N-(喹啉-8-基亚甲基)甲胺] (Mon-Pt-1) 和 [PtL2Cl]Cl [L2= (Z)-2-(吡啶-2-基)-N-(喹啉-8-基亚甲基)乙胺](Mon-Pt-2)。与顺铂相比，Mon-Pt-2 表现出更大的体外细胞毒性，对耐药细胞更有效，并引发更好的抗癌效果。机制实验表明，Mon-Pt-2 主要在线粒体中积累，并刺激显着的 TrxR 抑制 ROS 释放和由线粒体功能障碍介导的 ER 应激反应，最终导致同时诱导细胞凋亡和自噬。重要的是，与顺铂相比，Mon-Pt-2 在小鼠肿瘤模型中表现出较低的急性毒性和更好的抗癌活性。据我们所知，Mon-Pt-2 是第一个诱导癌细胞促死亡自噬和凋亡的单功能铂络合物。
Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands, [PtL1Cl]Cl [L1= (Z)-1-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) methanamine] (Mon-Pt-1) and [PtL2Cl]Cl [L2= (Z)-2-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) ethanamine] (Mon-Pt-2). In comparison to cisplatin, Mon-Pt-2 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that Mon-Pt-2 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition ROS release and an ER stress response, mediated by mitochondrial dysfunction, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, Mon-Pt-2 exhibits lower acute toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Mon-Pt-2 is the first mono-functional platinum complex inducing pro-death autophagy and apoptosis of cancer cells.