Ruthenium(II)/Benzonitrile Complex Induces Cytotoxic Effect in Sarcoma-180 Cells by Caspase-Mediated and Tp53 /p21-Media
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Ruthenium(II)/Benzonitrile Complex Induces Cytotoxic Effect in Sarcoma-180 Cells by Caspase-Mediated and Tp53/p21-Mediated Apoptosis, with Moderate Brine Shrimp Toxicity Raquel Santos Faria 1 & Hugo Delleon Silva 1,2 & Francyelli Mello-Andrade 1,3 & Wanessa Carvalho Pires 1 & Flávia de Castro Pereira 1 & Aliny Pereira de Lima 1,4 & Sônia de Fátima Oliveira Santos 1 & Thallita Monteiro Teixeira 1 & Paula Francinete Faustino da Silva 1 & Plínio Lázaro Faleiro Naves 5 & Alzir Azevedo Batista 6 & Renato José da Silva Oliveira 7 & Rui Manuel Reis 7 & Elisângela de Paula Silveira-Lacerda 1 Received: 1 November 2019 / Accepted: 26 February 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Ruthenium(II)/benzonitrile complexes have demonstrated promising anticancer properties. Considering that there are no specific therapies for treating sarcoma, we decided to evaluate the cytotoxic, genotoxic, and lethal effects of cis-[RuCl(BzCN)(phen)(dppb)]PF 6 (BzCN = benzonitrile; phen = 1,10-phenanthroline; dppb = 1,4bis-(diphenylphosphino)butane), as well as the mechanism of cell death induction that occurs against murine sarcoma-180 tumor. Thus, MTT assay was applied to assess the ruthenium cytotoxicity, showing that the compound is a more potent inhibitor for the sarcoma-180 tumor cell viability than normal cells (lymphocytes). The comet assay indicated low genotoxic for normal cells. cis-[RuCl(BzCN)(phen)(dppb)]PF6 also showed moderate lethality in Artemia salina. The complex induced cell cycle arrest in the G0/G1 phase in sarcoma-180 cells. In addition, the complex caused S180 cells to die by apoptosis by an increase in AnnexinV-positive cells and morphological changes typical of apoptotic cells. Additionally, cis-[RuCl(BzCN)(phen)(dppb)]PF6 increased the gene expression of Bax, Casp3, and Tp53 in S180 cells. By using a western blot, we observed an increased protein level of TNF-R2, Bax, and p21. In conclusion, cis-[RuCl(BzCN)(phen)(dppb)]PF6 is active and selective for sarcoma-180 cells, leading to cell cycle arrest at the G0/G1 and cell death through a caspases-mediated and Tp53/p21-mediated pathway. Keywords Sarcoma . Ruthenium . Apoptosis . DNA damage . Toxicity
Introduction Soft tissue sarcomas are a rare group of mesenchymal tumors, which can occur in any part within the body. They are more
prevalent in children, and pediatric sarcomas tend to be highly aggressive [1]. Identifying more effective therapeutic strategies to treat sarcomas is extremely important because, unfortunately, soft tissue sarcomas respond poorly to systemic
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12011-020-02098-8) contains supplementary material, which is available to authorized users. * Elisângela de Paula Silveira-Lacerda [email protected]
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Faculty of Brazil Institute (FIBRA), Anapolis, Goiás 75133-050, Brazil
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Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiá
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