Three Ru(II) complexes modulate the antioxidant transcription factor Nrf2 to overcome cisplatin resistance

Here, we designed, synthesized and characterized three new cyclometalated Ru(II) complexes, [Ru(phen)₂(1-(4-Ph-Ph)-IQ)]⁺ (phen = 1,10-phenanthroline, IQ = isoquinoline, RuIQ9), [Ru(phen)₂(1-(4-Ph-Ph)-7-OCH₃-IQ)]⁺ (RuIQ10), and [Ru(phen)₂(1-(4-Ph-Ph)-6,7-(OCH₃)₂-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.