Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1317119 | Journal of Inorganic Biochemistry | 2015 | 11 Pages |
•Ru(II)/diphosphine/diimine/benzonitrile complexes were obtained.•The complexes exerted effects over the tumor cells S180, DU145, K562 and A549.•The [RuCl(BzCN)(bipy)(dppe)]PF6 complex increases the expression of caspase-3.•The JC 1 test showed that the complex triggers apoptosis, probably through mitochondria.•The complexes probably act by extrinsic and intrinsic apoptosis pathways.
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 = benzonitrile; 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.
Graphical abstractThe illustration of the Ru(II) complex activating the intrinsic and extrinsic pathways of the carcinogenic cell shows the increased level of caspase 8 expression (originator) in addition to the increased level of protein caspase 3 (effector) triggered by the intrinsic pathway and most likely also by extrinsic passage.Figure optionsDownload full-size imageDownload as PowerPoint slide