Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, School of Pharmacy, Guangdong Medical University, Zhanjiang 524023, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, Guangdong 524023, China.
Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, School of Pharmacy, Guangdong Medical University, Zhanjiang 524023, China.
Bioorg Chem. 2022 Feb;119:105516. doi: 10.1016/j.bioorg.2021.105516. Epub 2021 Nov 25.
Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3, RuIQ-4, and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5, were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo. Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3β/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity.
钌（Ru）和异喹啉（IQ）化合物都被认为是有潜力的抗癌药物候选物。在这里，我们报告了三种新型的金属环戊二烯基钌（II）-异喹啉配合物的合成和表征：RuIQ-3、RuIQ-4 和 RuIQ-5，并评估了它们对一系列细胞系的体外细胞毒性，包括 A549/DDP，一种顺铂耐药的人肺癌细胞系。还使用 A549/DDP 三维多细胞肿瘤球体（MCTS）来检测 Ru(II)-IQ 配合物的耐药逆转作用。我们的结果表明，Ru(II)-IQ 配合物，尤其是 RuIQ-5，对癌细胞的细胞毒性活性优于顺铂。此外，RuIQ-5 对体外正常 HBE 细胞和体内斑马鱼胚胎的毒性较低。对细胞作用机制的进一步研究表明，RuIQ-5 被 A549/DDP 细胞吸收后，主要分布在细胞核中，这与顺铂不同。此外，RuIQ-5 可以通过线粒体功能障碍、活性氧（ROS）积累、ROS 介导的 DNA 损伤和 S 和 G2/M 期的细胞周期停滞诱导细胞凋亡。此外，RuIQ-5 可以通过调节 Akt/GSK-3β/Fyn 信号通路和阻碍 Nrf2 的核易位来抑制 Nrf2 的过表达。基于这些发现，我们坚信所研究的 Ru(II)-IQ 配合物具有作为高效低毒抗癌治疗剂的巨大潜力。
