Cytotoxicity in vitro, cell migration and apoptotic mechanism studies induced by ruthenium(II) complexes

Four new ruthenium(II) polypyridyl complexes [Ru(dmb)(2)(DHBT)](ClO4)(2) (1) (DHBT - 12,14-dihydroxyl-4,5,9,10,11,13-hexaazabenzo[b]triphenylene, dmb = 4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)(2)(DHBT)](ClO4)(2) (2) (bpy = 2,2'-bipyridine), [Ru(phen)(2)(DHBT)](ClO4)(2) (3) (phen = 1,10-phenanthroline) and [Ru(dmp)(2)(DHBT)](ClO4)(2) (4) (dmp = 2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized. The cytotoxicity in vitro of these complexes was evaluated against human HepG-2, HeLa, A549, MG-63 and BEL-7402 cancer cell lines. The IC50 values of the complexes toward selected cell lines range from 14.9 +/- 1.1 to 30.1 +/- 2.7 mu M. The cytotoxicity and the levels of reactive oxygen species were found to increase with increasing concentrations of the complexes. The complexes are sensitive to MG-63 cells and can inhibit the MG-63 cell migration. Morphological and comet assay studies show that the complexes can effectively induce apoptosis in MG-63 cells. Complex 2 inhibits the cell growth at the G0/G1 phase, whereas the other complexes exhibit the antiproliferative mechanism at the S phase in the MG-63 cell line. The complexes can downregulate the expression of Bcl-2 protein and upregulate the levels of Bad protein in MG-63 cells. The complexes induce MG-63 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway.