cis-[RuCl(BzCN)(bipy)(dppe)]PF6 induces anti-angiogenesis and apoptosis by a mechanism of caspase-dependent involving DNA damage, PARP activation, and Tp53 induction in Ehrlich tumor cells

Antimetastatic activities, low toxicity to normal cells and high selectivity for tumor cells make of the ruthenium complexes promising candidates in the search for develop new chemotherapeutic agents for the treatment of cancer. This study aimed to determine the cytotoxic, genotoxic and to elucidate...

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Published in:	Chemico-biological interactions Vol. 278; pp. 101 - 113
Main Authors:	Magalhães, Lorena Félix, Mello-Andrade, Francyelli, Pires, Wanessa Carvalho, Silva, Hugo Delleon, da Silva, Paula Francinete Faustino, Macedo, Larissa Matuda, Henrique de Castro, Carlos, Carneiro, Cristiene Costa, Cardoso, Clever Gomes, de Melo Reis, Paulo Roberto, Camargo de Oliveira, Laís, Caetano, Renata Rodrigues, Batista, Alzir A., Silveira-Lacerda, Elisângela de Paula
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier B.V 25-12-2017
Subjects:	Adult Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Carcinoma, Ehrlich Tumor - blood supply Carcinoma, Ehrlich Tumor - metabolism Carcinoma, Ehrlich Tumor - pathology Cell cycle Cells, Cultured Chick Embryo Chickens Chorioallantoic Membrane - blood supply Chorioallantoic Membrane - pathology Coordination Complexes - chemistry Coordination Complexes - pharmacology Coordination Complexes - toxicity DNA damage DNA Damage - drug effects Ehrlich G1 Phase Cell Cycle Checkpoints - drug effects Humans Leukocytes, Mononuclear - cytology Leukocytes, Mononuclear - metabolism Mice Neovascularization, Physiologic - drug effects Poly(ADP-ribose) Polymerases - metabolism Ruthenium Ruthenium - chemistry Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Young Adult Ruthenium DNA damage Ehrlich Cell cycle Apoptosis
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Summary:	Antimetastatic activities, low toxicity to normal cells and high selectivity for tumor cells make of the ruthenium complexes promising candidates in the search for develop new chemotherapeutic agents for the treatment of cancer. This study aimed to determine the cytotoxic, genotoxic and to elucidate the signaling pathway involved in the death cell process induced by cis-[RuCl(BzCN)(bipy)(dppb)]PF6(1) and cis-[RuCl(BzCN)(bipy)(dppe)]PF6(2) in Ehrlich ascites carcinoma (EAC) in vitro. Moreover, we report for the first time the anti-angiogenic potential on chick embryo chorioallantoic membrane (CAM) model. Peripheral blood mononuclear cells (PBMC) were isolated from healthy controls with an age range of 20–30 years and used to calculate the selectivity index (SI). The complex 2 (IC50 = 8.5 ± 0.4/SI = 6.3) showed high cytotoxic and selectivity index against EAC cells than complex 1 (IC50 = 14.9 ± 0.2/SI = 0.2) using the MTT assay. Complex 2 induced DNA damage on Ehrlich tumor cells at concentrations and time periods evalueted. In consequence, it was observed an increase of Tp53 gene expression, G0/G1-arrest cells, and increased levels of cleaved PARP protein. Beside that, the treatment of EAC with complex 2 led to an increase in Annexin V-positive cells and apoptosis induction by Caspase-7. Additionally, the complex 2 inhibited the angiogenesis caused by Ehrlich tumor cells in CAM model. This complex is active and selective for Ehrlich tumor cells, inducing DNA damage, cell cycle arrest and cell death by caspase-dependent apoptosis involving PARP activation (PARP1), and Tp53 induction. •cis-[RuCl(BzCN)(bipy)(dppe)]PF6 shows selective cytotoxicity towards EAC cells.•The complex caused DNA damage, p53 activation and cell cycle arrest at G0/G1 phase.•The complex caused changes in gene expression of Tp53, Bax and Caspase 9.•The complex induced apoptosis through a caspase-7-independent with PARP activation.•cis-[RuCl(BzCN)(bipy)(dppe)]PF6 inhibited the angiogenesis in CAM model.
ISSN:	0009-2797 1872-7786
DOI:	10.1016/j.cbi.2017.09.013