The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, Guangdong 524023, China; Key Laboratory of Computer-Aided Drug Design of Dongguan City, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China.
The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, Guangdong 524023, China.
J Inorg Biochem. 2024 Oct;259:112666. doi: 10.1016/j.jinorgbio.2024.112666. Epub 2024 Jul 14.
Here, we designed, synthesized and characterized three new cyclometalated Ru(II) complexes, [Ru(phen)(1-(4-Ph-Ph)-IQ)] (phen = 1,10-phenanthroline, IQ = isoquinoline, RuIQ9), [Ru(phen)(1-(4-Ph-Ph)-7-OCH-IQ)] (RuIQ10), and [Ru(phen)(1-(4-Ph-Ph)-6,7-(OCH)-IQ)] (RuIQ11). The cytotoxicity experiments conducted on both 2D and 3D multicellular tumor spheroids (MCTSs) indicated that complexes RuIQ9-11 exhibited notably higher cytotoxicity against A549 and A549/DDP cells when compared to the ligands and precursor compounds as well as clinical cisplatin. Moreover, the Ru(II) complexes displayed low toxicity when tested on normal HBE cells in vitro and exposed to zebrafish embryos in vivo. In addition, complexes RuIQ9-11 could inhibit A549 and A549/DDP cell migration and proliferation by causing cell cycle arrest, mitochondrial dysfunction, and elevating ROS levels to induce apoptosis in these cells. Mechanistic studies revealed that RuIQ9-11 could suppress the expression of Nrf2 and its downstream antioxidant protein HO-1 by inhibiting Nrf2 gene transcription in drug-resistant A549/DDP cells. Simultaneously, they inhibited the expression of efflux proteins MRP1 and p-gp in drug-resistant cells, ensuring the accumulation of the complexes within the cells. This led to an increase in intracellular ROS levels in drug-resistant cells, ultimately causing damage and cell death, thus overcoming cisplatin resistance. More importantly, RuIQ11 could effectively inhibit the migration and proliferation of drug-resistant cells within zebrafish, addressing the issue of cisplatin resistance. Accordingly, the prepared Ru(II) complexes possess significant potential for development as highly effective and low-toxicity lung cancer therapeutic agents to overcome cisplatin resistance.
在这里，我们设计、合成并表征了三个新的环金属化 Ru(II)配合物，[Ru(phen)(1-(4-Ph-Ph)-IQ)]（phen=1,10-菲咯啉，IQ=异喹啉，RuIQ9）、[Ru(phen)(1-(4-Ph-Ph)-7-OCH-IQ)]（RuIQ10）和[Ru(phen)(1-(4-Ph-Ph)-6,7-(OCH)-IQ)]（RuIQ11）。在二维和三维多细胞肿瘤球体（MCTS）上进行的细胞毒性实验表明，与配体和前体化合物以及临床顺铂相比，配合物 RuIQ9-11 对 A549 和 A549/DDP 细胞表现出明显更高的细胞毒性。此外，这些 Ru(II)配合物在体外测试对正常 HBE 细胞的毒性较低，在体内暴露于斑马鱼胚胎时毒性也较低。此外，配合物 RuIQ9-11 可以通过引起细胞周期停滞、线粒体功能障碍和增加 ROS 水平来诱导细胞凋亡，从而抑制 A549 和 A549/DDP 细胞的迁移和增殖。机制研究表明，RuIQ9-11 可以通过抑制耐药 A549/DDP 细胞中 Nrf2 基因转录来抑制 Nrf2 及其下游抗氧化蛋白 HO-1 的表达。同时，它们抑制了耐药细胞中流出蛋白 MRP1 和 p-gp 的表达，确保了配合物在细胞内的积累。这导致耐药细胞内的 ROS 水平增加，最终导致细胞损伤和死亡，从而克服顺铂耐药性。更重要的是，RuIQ11 可以有效地抑制斑马鱼内耐药细胞的迁移和增殖，解决了顺铂耐药性的问题。因此，所制备的 Ru(II)配合物具有作为克服顺铂耐药性的高效低毒肺癌治疗剂的巨大潜力。
Zotero 插件