8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin

Ruthenium complexes are one of the most promising anticancer drugs triggered extensive research. Here, the synthesis and characterization of two ruthenium(II) polypyridine complexes containing 8-hydroxylquinoline as ligand, [Ru(dip)₂(8HQ)]PF₆ (Ru1), [Ru(dpq)₂(8HQ)]PF₆ (Ru2) (8HQ = 8-hydroxylquinoline; dip = 4,7-diphenyl-1,10-phenanthroline; dpq = pyrazino[2,3-f][1,10]phenanthroline) were reported. On the basis of cytotoxicity tests, Ru1 (IC₅₀ = 1.98 ± 0.02 μM) and Ru2 (IC₅₀ = 10.02 ± 0.19 μM) both showed good anticancer activity in a panel of cell lines, especially in HeLa cells. Researches on mechanism indicated that Ru1 and Ru2 acted on mitochondria and nuclei and induced reactive oxygen species (ROS) accumulation, while the morphology of nuclei and cell cycle had no significant change. Western blot assay further proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in HeLa cells. In addition, the toxicity test of zebrafish embryos showed that the concentrations of Ru1 and Ru2 below 120 μM and 60 μM were safe and did not have obvious effect on the normal development of zebrafish embryos.