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

  • Aliny Pereira de Lima
  • Marcio Aurélio Pinheiro Almeida
  • Francyelli Mello-Andrade
  • Flávia de Castro Pereira
  • Wanessa Carvalho Pires
  • Davi Carvalho Abreu
  • Vivianne de Souza Velozo-Sá
  • Alzir Azevedo Batista
  • Elisângela de Paula Silveira-LacerdaEmail author
Article

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.

Keywords

Leukemia  Mitochondria dysfunction  DNA damage  Apoptosis 

Notes

Funding information

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).

Compliance with Ethical Standards

Conflict of Interest

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological SciencesFederal University of GoiásGoiâniaBrazil
  2. 2.Faculty of Brazil Institute (FIBRA)AnápolisBrazil
  3. 3.Coordination of Science and TechnologyFederal University of MaranhãoSão LuísBrazil
  4. 4.Department of ChemistryFederal Institute of Education, Science and Technology of GoiásGoiâniaBrazil
  5. 5.Department of ChemistryFederal University of São CarlosSão CarlosBrazil

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