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Mitochondria-targeted cyclometalated iridium (III) complexes: Dual induction of A549 cells apoptosis and autophagy.
Chen, Lanmei; Tang, Hong; Chen, Weigang; Wang, Jie; Zhang, Shenting; Gao, Jie; Chen, Yu; Zhu, Xufeng; Huang, Zunnan; Chen, Jincan.
Afiliación
  • Chen L; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanj
  • Tang H; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanj
  • Chen W; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China.
  • Wang J; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China.
  • Zhang S; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanj
  • Gao J; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanj
  • Chen Y; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China.
  • Zhu X; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong 524023, PR China. Electronic address: xufeng910730@126.com.
  • Huang Z; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanj
  • Chen J; Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanj
J Inorg Biochem ; 249: 112397, 2023 12.
Article en En | MEDLINE | ID: mdl-37844533
In this study, we synthesized 4 cyclometalated iridium complexes using N-(1,10-phenanthrolin-5-yl)picolinamide (PPA) as the main ligand, denoted as [Ir(ppy)2PPA]PF6 (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2PPA]PF6 (bzq = benzo[h]quinoline, Ir2), [Ir(dfppy)2PPA]PF6 (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy)2PPA]PF6 (thpy = 2-(thiophene-2-yl)pyridine, Ir4). Compared to cisplatin and oxaliplatin, all four complexes exhibited significant anti-tumor activity. Among them, Ir2 demonstrated higher cytotoxicity against A549 cells, with an IC50 value of 1.6 ± 0.2 µM. The experimental results indicated that Ir2 primarily localized in the mitochondria, inducing a large amount of reactive oxygen species (ROS) generation, that decreased in mitochondrial membrane potential (MMP), reduced ATP production, and further impaired mitochondrial function, leading to cytochrome c release. Additionally, Ir2 caused cell cycle arrest at the S phase and induced apoptosis through the AKT-mediated signaling pathway. Further investigations revealed that Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells, with the latter acting as a non-protective mechanism that promoted cell death. More importantly, Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. Consequently, these newly developed Ir(III) complexes show great potential in the development of novel and low-toxicity anticancer agents.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complejos de Coordinación / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: J Inorg Biochem Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complejos de Coordinación / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: J Inorg Biochem Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos