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Ru(II)-Based Amino Acid Complexes Show Promise for Leukemia Treatment: Cytotoxicity and Some Light on their Mechanism of Action

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Abstract

Ruthenium is attracting considerable interest as the basis for new compounds to treat diseases, and studies have shown that complexes with different structures have significant antineoplastic and antimetastatic potential against several types of tumors, including tumors resistant to cisplatin drugs. We examined the cytotoxic, genotoxic, and pro-apoptotic activities of six ruthenium complexes containing amino acid with general formulation [Ru(AA)(bipy)(dppb)]PF6, where AA = amino acid (alanine, glycine, leucine, lysine, methionine, or tryptophan); bipy = 2,2´-bipyridine; and dppb = [1,4-bis(diphenylphosphine)butane], against A549 (lung carcinoma) and K562 (chronic myelogenous leukemia) cancer cells. The results show that the ruthenium complexes tested were able to induce cytotoxicity in A549 and K562 cancer cells. Complex 1 containing alanine inhibited the cell viability of A549 and K562 tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and the induction of DNA damage and cell cycle arrest. Complex 1 was able to induce caspase-mediated apoptosis in K562 cells through the mitochondrial dysfunction, the upregulation of apoptotic genes, and the downregulation of Bcl2 anti-apoptotic gene. Besides being cytotoxic to K562 and A549 cells, ruthenium complex containing alanine shows low cytotoxicity and genotoxicity against non-tumor cells. These results suggest that the ruthenium (II) complex is a potential safe and efficient antineoplastic candidate for leukemia treatment.

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Funding

This study was funded by Brazilian research financing institutions: Foundation for Research Support of the State of Maranhão (FAPEMA) [grant number PPP-02100/14], and Brazilian National Counsel of Technological and Scientific Development (CNPq) (grant number 454266/2014-6 and 31960/2008-3).

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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, Goiânia, Goiás, 74690-900, Brazil

    Aliny Pereira de Lima, Francyelli Mello-Andrade, Flávia de Castro Pereira, Wanessa Carvalho Pires, Davi Carvalho Abreu, Vivianne de Souza Velozo-Sá & Elisângela de Paula Silveira-Lacerda

  2. Faculty of Brazil Institute (FIBRA), Anápolis, Goiás, 75133-050, Brazil

    Aliny Pereira de Lima

  3. Coordination of Science and Technology, Federal University of Maranhão, São Luís, Maranhão, 65080-805, Brazil

    Marcio Aurélio Pinheiro Almeida

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

    Francyelli Mello-Andrade

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

    Alzir Azevedo Batista

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  1. Aliny Pereira de Lima
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Correspondence to Elisângela de Paula Silveira-Lacerda.

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The authors declare that they have no conflict of interest or no financial conflict of interest to disclose. The authors Aliny Pereira de Lima, Márcio Aurélio Pinheiro Almeida, Francyelli Mello-Andrade, Alzir Azevedo Batista, and Elisângela de Paula Silveira-Lacerda report have a national patent application filing (number patent BR1020130336041A2).

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de Lima, A.P., Almeida, M.A.P., Mello-Andrade, F. et al. Ru(II)-Based Amino Acid Complexes Show Promise for Leukemia Treatment: Cytotoxicity and Some Light on their Mechanism of Action . Biol Trace Elem Res 197, 123–131 (2020). https://doi.org/10.1007/s12011-019-01976-0

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