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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

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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)]PF6 (BzCN = benzonitrile; phen = 1,10-phenanthroline; dppb = 1,4-bis-(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 Annexin-V-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.

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Authors and Affiliations

  1. Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Avenida Esperança, s/n, Campus Samambaia (Campus II), Cx. Postal 131, Goiania, GO, 74690-900, Brazil

    Raquel Santos Faria, Hugo Delleon Silva, Francyelli Mello-Andrade, Wanessa Carvalho Pires, Flávia de Castro Pereira, Aliny Pereira de Lima, Sônia de Fátima Oliveira Santos, Thallita Monteiro Teixeira, Paula Francinete Faustino da Silva & Elisângela de Paula Silveira-Lacerda

  2. Uni-Anhanguera University Center of Goias, Goiania, Goiás, 74423-115, Brazil

    Hugo Delleon Silva

  3. Department of Chemistry, Federal Institute of Education, Science and Technology of Goiás, Goiania, Goiás, 74055-110, Brazil

    Francyelli Mello-Andrade

  4. Faculty of Brazil Institute (FIBRA), Anapolis, Goiás, 75133-050, Brazil

    Aliny Pereira de Lima

  5. Campus of Exact and Technological Sciences, State University of Goiás, Anapolis, Goiás, 75110-390, Brazil

    Plínio Lázaro Faleiro Naves

  6. Department of Chemistry, Federal University of São Carlos, Sao Carlos, São Paulo, 13565-905, Brazil

    Alzir Azevedo Batista

  7. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, 14784-400, Brazil

    Renato José da Silva Oliveira & Rui Manuel Reis

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  1. Raquel Santos Faria
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Faria, R.S., Silva, H.D., Mello-Andrade, F. et al. Ruthenium(II)/Benzonitrile Complex Induces Cytotoxic Effect in Sarcoma-180 Cells by Caspase-Mediated and Tp53/p21-Mediated Apoptosis, with Moderate Brine Shrimp Toxicity. Biol Trace Elem Res 198, 669–680 (2020). https://doi.org/10.1007/s12011-020-02098-8

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