Mitochondria-targeted platinum(II) complexes induce apoptosis-dependent autophagic cell death mediated by ER-stress in A549 cancer cells

Abstract

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.