Synthesis and anticancer properties of ruthenium (II) complexes as potent apoptosis inducers through mitochondrial disruption

Abstract

A new ligand MHPIP (MHPIP = 2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its three ruthenium (II) complexes [Ru(N-N)2(MHPIP)](ClO4)2 (N-N = phen: 1,10-phenanthroline 1; dmp = 2,9-dimethyl-1,10-phenanthroline 2; ttbpy = 4,4′-ditertiarybutyl-2,2′-bipyridine 3) were synthesized and characterized. The cytotoxic activity in vitro was studied by MTT method. The complexes 1–3 show moderate cytotoxic effects on the cell growth in HepG2 cells with an IC50 value of 25.5 ± 3.5, 35.6 ± 1.9 and 27.4 ± 2.3 μM, respectively. The apoptosis was investigated with AO/EB and Annex V/PI staining methods and comet assay. The reactive oxygen species, mitochondrial membrane potential were investigated under a fluorescent microscope. Autophagy assay shows that the complexes can cause autophagy and up-regulate the expression of Beclin-1 protein. Additionally, the complexes inhibit the cell growth in HepG2 cells at G0/G1 phase, and the complexes can regulate the expression of caspase 3 and Bcl-2 family proteins. The studies demonstrate that the complexes induce apoptosis in HepG2 cells through DNA damage and ROS-mediated mitochondrial dysfunction pathways.