Synthesis, characterization and anticancer activity studies of ruthenium(II) polypyridyl complexes on A549 cells.
Four new ruthenium(II) polypyridyl complexes [Ru(N-N)2(bddp)](ClO4)21-4 (N-N=dmb: 4,4'-dimethyl-2,2'-bipyridine 1, bpy: 2,2'-bipyridine 2, phen: 1,10-phenanthroline 3 and dmp: 2,9-dimethyl-1,10-phenanthroline 4, bddp=benzilo[2,3-b]-1,4-diazabenzo[i]dipyrido[3,2-a:2',3'-c]phenazine) were synthesized and characterized by elemental analysis, ESI-MS and (1)H NMR. The cytotoxicity in vitro of the complexes against BEL-7402, HeLa, MG-63 and A549 cell lines was investigated by MTT method. The complexes show high cytotoxic activity toward the selected cell lines with an IC50 value ranging from 5.3±0.6 to 15.7±3.6μM. The apoptosis was studied with acridine orange (AO)/ethdium bromide (EB) and Hoechst 33258 staining methods. The cellular uptake was investigated with DAPI staining method. The reactive oxygen species (ROS) and mitochondrial membrane potential were performed under fluorescent microscope and flow cytometry. The complexes can induce an increase in the ROS levels and a decrease in the mitochondrial membrane potential. The comet assay was studied with fluorescent microscope. The percentage in apoptotic and necrotic cells and cell cycle arrest were assayed by flow cytometry. The effects of the complexes on the expression of caspases and Bcl-2 family proteins were studied by western blot analysis. The results show that the complexes induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulating the expression of Bcl-2 family proteins.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Chuan-Chuan
CC
Zeng
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Guang-Bin
GB
Jiang
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Shang-Hai
SH
Lai
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.
Bing
B
Tang
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Dan
D
Wan
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: lyjche@163.com.
Yun-Jun
YJ
Liu
D015082:2,2'-Dipyridyl / Q000737:chemistry; D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D020552:Comet Assay; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D053938:DNA Fragmentation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008856:Microscopy, Fluorescence; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D015082:2,2'-Dipyridyl; D012428:Ruthenium; D020169:Caspases
Apoptosis; Cell cycle arrest; Cellular uptake; Ru(II) complex; Western blot analysis