title: Cis-[RuCl(BzCN)(N-N)(P-P)]PF6 complexes: Synthesis and in vitro antitumor activity: (BzCN=benzonitrile; N-N=2,2'-bipyridine; 1,10-phenanthroline; P-P=1,4-bis(diphenylphosphino) butane, 1,2-bis(diphenylphosphino)ethane, or 1,1'-(diphenylphosphino)ferrocene).
abstract: The motivation to use ruthenium complexes in cancer treatment has led our research group to synthesize complexes with this metal and test them against several types of tumor cells, yielding promising results. In this paper the results of biological tests, assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, were carried out on the complexes cis-[RuCl(BzCN)(bipy)(dppe)]PF6 (1), cis-[RuCl(BzCN)(bipy)(dppb)]PF6 (2), cis-[RuCl(BzCN)(bipy)(dppf)]PF6 (3) and cis-[RuCl(BzCN)(phen)(dppb)]PF6 (4) which are described [BzCN = b enzonitrile; bipy = 2,2'-bipyridine; phen = 1,10-phenanthroline; dppe = 1,2-bis(diphenylphosphino) ethane; dppb = 1,4-bis-(diphenylphosphino)butane; dppf = 1,1'-bis(diphenylphosphino)ferrocene]. The present study is focused on the cytotoxic activity of complexes (1)-(4) against four tumor cell lines and on the apoptosis and changes in the cell cycle and gene expression observed in the sarcoma 180 (S180) tumor cell line treated with complex (1). The results demonstrated that this complex inhibits S180 cell growth, with an IC50 of 17.02 ± 8.21 μM, while exhibiting lower cytotoxicity (IC50 = 53.73 ± 5.71 μM) towards lymphocytes (normal cells). Flow cytometry revealed that the complex inhibits the growth of tumor cells by inducing apoptosis as evidenced by an increase in the proportion of cells positive for annexin V staining and G0/G1 phase cell-cycle arrest. Further investigation showed that complex (1) induces a drop in the mitochondrial membrane potential and provokes a decrease in Bcl-2 protein expression and increase in caspase 3 activation, while the increased activation of caspase 8 caused a decrease in the gene expression in caspases 3 and 9. Increases in Tp53 and Bax expressions were also observed.
authors: Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil.
authors: Flávia de C
authors: Fde C
authors: Pereira
authors: Department of Chemistry, Federal University of São Carlos, São Carlos, SP CEP 13.565-905, Brazil.
authors: Benedicto A V
authors: BA
authors: Lima
authors: Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil.
authors: Aliny P
authors: AP
authors: de Lima
authors: Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil.
authors: Wanessa C
authors: WC
authors: Pires
authors: Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil.
authors: Thallita
authors: T
authors: Monteiro
authors: Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil.
authors: Lorena F
authors: LF
authors: Magalhães
authors: Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil.
authors: Wanderson
authors: W
authors: Costa
authors: Department of Chemistry, Federal University of São Carlos, São Carlos, SP CEP 13.565-905, Brazil.
authors: Angélica E
authors: AE
authors: Graminha
authors: Department of Chemistry, Federal University of São Carlos, São Carlos, SP CEP 13.565-905, Brazil. Electronic address: daab@ufscar.br.
authors: Alzir A
authors: AA
authors: Batista
authors: São Carlos Institute of Physics, University of São Paulo, São Carlos, SP CEP 13560-970, Brazil.
authors: Javier
authors: J
authors: Ellena
authors: Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil. Electronic address: silveiralacerda@gmail.com.
authors: Elisângela de P
authors: Ede P
authors: Siveira-Lacerda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D012428:Ruthenium / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D012428:Ruthenium
keywords: Apoptosis induction; Chemotherapeutic agent; Expression of pro-apoptotic genes; Ruthenium complexes; Sarcoma 180