Ruthenium(II) polypyridyl complexes: Synthesis, characterization and anticancer activity studies on BEL-7402 cells

Two new ligand PTTP (2-phenoxy-1,4,8,9-tetraazatriphenylene) and FTTP (2-(3-fluoronaphthalen-2-yloxy)1,4,8,9-tetraazatriphenylene) and their six ruthenium(II) polypyridyl complexes [Ru(N-N)(2)(PTTP)] (ClO4)(2) and [Ru(N-N)(2)(FTTP)])(ClO4)(2) (N-N = dmb: 4,4'-dimethyl-2,2'-bipiridine; dmp: 2,9-dimethyl-1,10-phenanthroline; ttbpy: 4,4'-ditertiarybutyl-2,2'-bipyridine) were synthesized and characterized. The cytotoxic activity of the complexes against cancer cells HeLa, BEL-7402, A549, HepG-2, HOS and normal cell LO2 was evaluated by MTT method. The IC50 values range from 1.5 +/- 0.1 to 55.9 +/- 7.5 mu M. Complex 3 shows the highest cytotoxic activity toward BEL-7402 cells (IC50 = 1.5 +/- 0.1 mu M). Complex 5 displays most effective inhibition of the cell growth in A549 and HOS cells with low IC50 values of 2.5 +/- 0.6 and 2.6 +/- 0.1 mu M, respectively. The apoptosis, reactive oxygen species, mitochondrial membrane potential, DNA damage, autophagy and anti metastasis assay were investigated under a fluorescent microscope. The cell cycle arrest was assayed by flow cytometry, and the expression of caspases and Bcl-2 family proteins was studied by western blot. The results obtained show that the complexes induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondria dysfunction pathway.