Ruthenium(II) salicylate complexes inducing ROS-mediated apoptosis by targeting thioredoxin reductase

Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. TrxR has become an attractive target for anticancer agents . In this work, three Ru(II) complexes with salicylate as ligand, [Ru(phen) 2 (SA)] (phen = 1,10-phenanthroline, SA = salicylate, 1 ), [Ru(dmb) 2 (SA)] (dmb = 4,4′-dimethyl-2,2′-bipyridine, 2 ) and [Ru(bpy) 2 (SA)] (bpy = 2,2′-bipyridine, 3 ), were synthesized and characterized. The anticancer effect exerted by them was evaluated. Complex 1 was found to exhibit obvious anticancer activity , in comparison with cisplatin , against cancer cell lines, while displaying low toxicity to the normal cell line BEAS-2B. The mechanism of complex 1 cancer cell growth suppress was investigated in A549 cells. Complex 1 exerted its anticancer through inducing apoptosis and triggering cell cycle arrest at the G0/G1 phase. Complex 1 can selectively inhibit TrxR activity and thus promote the generation and accumulation of reactive oxygen species (ROS), which subsequently trigger mitochondrial dysfunction and DNA damage, activate oxidative stress-sensitive mitogen activated protein kinase (MAPK), and suppress the protein kinase B (PKB or AKT) signal pathway, resulting in apoptosis in A549 cells.