title: Ruthenium(II) polypyridyl complexes induce BEL-7402 cell apoptosis by ROS-mediated mitochondrial pathway.
abstract: A new ligand dmdppz and its four ruthenium(II) polypyridyl complexes [Ru(dmb)2(dmdppz)](ClO4)2 (1), [Ru(bpy)2(dmdppz)](ClO4)2 (2), [Ru(phen)2(dmdppz)](ClO4)2 (3) and [Ru(dmp)2(dmdppz)](ClO4)2 (4) (where dmb, bpy, phen, dmp and dmdppz stand for 4,4'-dimethyl-2,2'-bipyridine, 2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline and 5,8-dimethoxylpyrido[3,2-a:2',3'-c]phenazine, respectively) have been synthesized and characterized. Their DNA binding behaviors show that the complexes bind to calf thymus DNA by intercalation. The complexes exhibit efficient photocleavage of pBR322 DNA on irradiation. The cytotoxicity of the ligand and the complexes toward HepG-2, HeLa, MG-63, A549 and BEL-7402 were assayed by MTT ((3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide)) method. The IC50 values of the complexes 1, 2, 3 and 4 toward BEL-7402 cells are 14.6, 16.8, 18.0 and 16.7 μM, respectively. Dmdppz shows no cytotoxic activity against selected cell lines. The cellular uptake, apoptosis, comet assay, reactive oxygen species (ROS), mitochondrial membrane potential and western blot analysis were investigated. These results indicate that complexes 1-4 exert their toxicity through the intrinsic ROS-mediated mitochondrial pathway, which is accompanied by the regulation of Bcl-2 family proteins.
authors.affiliation: School of Pharmacy, Guangdong Pharmaceutical University,Guangzhou, 510006, PR China.
authors.forename: Guang-Bin
authors.initials: GB
authors.lastname: Jiang
authors.affiliation: The Frst Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510062, PR China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Instrumentation Analysis and Research Center, Sun Yat-Sen University, Guangzhou, 510275, PR China.
authors.forename: Jun-Hua
authors.initials: JH
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Guangdong Pharmaceutical University,Guangzhou, 510006, PR China.
authors.forename: Bing-Jie
authors.initials: BJ
authors.lastname: Han
authors.affiliation: School of Pharmacy, Guangdong Pharmaceutical University,Guangzhou, 510006, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Pharmacy, Guangdong Pharmaceutical University,Guangzhou, 510006, PR China.
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Life Science and Biopharmaceutical, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address: hhongliang@163.com.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Guangdong Pharmaceutical University,Guangzhou, 510006, PR China. Electronic address: lyjche@163.com.
authors.forename: Yun-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003603:Cytotoxins; D007364:Intercalating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D017382:Reactive Oxygen Species; D012428:Ruthenium; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin
keywords: Comet assay; Cytotoxicity; Mitochondrial membrane potential; ROS; Ruthenium(II) polypyridyl complex; Western blot analysis