Synthesis, characterization and anticancer effect of the ruthenium (II) polypyridyl complexes on HepG2 cells.
As one of the major cell regulated center, mitochondria are closely associated with cell proliferation, apoptosis of tumor cell. In this work, four new ruthenium (II) polypyridyl complexes [Ru(bpy)2(FTTP)](ClO4)2(1) (FTTP=11-(3-fluoro-naphthalen-2-yloxy)-4,5,9,14-tetraaza-benzo[b]triphenylene, bpy=2,2'-bipyridine), [Ru(phen)2(FTTP)](ClO4)2(2) (phen=1,10-phenanthroline), [Ru(bpy)2(PTTP)](ClO4)2(3) (PTTP=2-phenoxy-1,4,8,9-tetraazatriphenylene) and [Ru(phen)2(PTTP)](ClO4)2(4) were synthesized and characterized by elemental analysis, ESI-MS,1H NMR and13C NMR. The cytotoxic activity, ability of inhibiting cell invasion, cell cycle arrest and apoptosis-inducing mechanism of these Ru(II) complexes have been investigated in detail by MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide) method, invasion assay, comet assay as well as western blotting techniques. Notably, complexes 1-4 displayed high cytotoxic activity against liver carcinoma HepG2 cells and the IC50values of complexes 1-4 against HepG2 cells are 10.4±1.2, 9.3±0.6, 29.1±1.5 and 5.6±1.2μM, respectively. The comet assay showed that the complexes can induce DNA damage. The acridine orange (AO) and ethidium bromide (EB) staining method indicated that the complexes can cause apoptosis in HepG2 cells. Further studies showed that complexes 1-4 caused cell cycle arrest at G0/G1 phase and induced HepG2 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway, which involved an increase in the levels of reactive oxygen species (ROS), a decrease in the mitochondrial membrane potential, activation of caspases and Bcl-2 family proteins.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Dan
D
Wan
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Shang-Hai
SH
Lai
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Hui-Hui
HH
Yang
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Bing
B
Tang
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Cheng
C
Zhang
Department of Microbiology and Immunology, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: huiyin0103@163.com.
Hui
H
Yin
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Chuan-Chuan
CC
Zeng
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Cosmetics Engineering & Technology Research Center, Guangzhou 510006, PR China. Electronic address: lyjche@163.com.
Yun-Jun
YJ
Liu
D017209:Apoptosis; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D004249:DNA Damage; D056945:Hep G2 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D066244:Proton Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
D011725:Pyridines; D017382:Reactive Oxygen Species; D012428:Ruthenium
Cell invasion; Cytotoxicity in vitro; Mitochondrial membrane potential; Reactive oxygen species; Ruthenium (II) polypyridyl complexes; Western blot analysis