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Ru(II)/diphenylphosphine/pyridine-6-thiolate complexes induce S-180 cell apoptosis through intrinsic mitochondrial pathway involving inhibition of Bcl-2 and p53/Bax activation

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Abstract

The aim of this work was the synthesis, characterization, and cytotoxicity evaluation of three new Ru(II) complexes with a general formula [Ru(Spy)(bipy)(P-P)]PF6 [Spy = pyridine-6-thiolate; bipy = 2,2′-bipyridine; P-P = 1,2-bis(diphenylphosphine)ethane (1); 1,3-bis(diphenylphosphine) propane (2); and 1,1′-bis(diphenylphosphino)ferrocene] (4). Complex (3) with the 1,4-bis(diphenylphosphine)butane ligand, already known from the literature, was also synthesized, to be better studied here. The cytotoxicities of the complexes toward two kinds of cancerous cells (K562 and S-180 cells) were evaluated and compared to normal cells (L-929 and PBMC) by MTT assay. The complex [Ru(Spy)(bipy)(dppb)]PF6 (3) was selected to study both the cellular and molecular mechanisms underlying its promising anticancer action in S-180 cells. The results obtained from this study indicated that complex (3) induces cell cycle arrest in the G0/G1 phase in S-180 cells associated with a decrease in the number of cells in S phase. After 24 and 48 h of exposure to complex (3), the cell viability decreased when compared to the negative control. Complex (3) does not appear to be involved in the DNA damage, but induced changes in the mitochondrial membrane potential in S-180 cells. Furthermore, there was also an increase in the gene expression of Bax, Caspase 9, and Tp53. According to our results, complex (3) induces cell apoptosis through p53/Bax-dependent intrinsic pathway and suppresses the expression of active antiapoptotic Bcl-2 protein.

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Acknowledgements

The authors gratefully acknowledge the financial support from Research and Project Financing (FINEP) (Grant No. 01.06.0941.00/CT-Saúde to Dr. Elisângela de Paula Silveira-Lacerda), the São Paulo Research Foundation (FAPESP) (Process 2014/10516-7) and from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. They would also like to thank the Coordination for the Improvement of Higher Education Personnel (CAPES) for the fellowship to Wanessa Carvalho Pires.

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Authors and Affiliations

  1. Laboratório de Genética Molecular e Citogenética, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, GO, 74690-900, Brazil

    Wanessa Carvalho Pires, Flávia de Castro Pereira, Aliny Pereira Lima, Francyelli Mello-Andrade, Hugo Delleon Silva & Elisângela de Paul Silveira-Lacerda

  2. Departamento de Química, Universidade Federal de São Carlos, P.O. Box 676, São Carlos, 13565-905, Brazil

    Benedicto Augusto Vieira Lima, Monize Martins da Silva, Legna Colina-Vegas & Alzir A. Batista

  3. Instituto de Física de São Carlos, Universidade de São Paulo, P.O. Box 369, São Carlos, SP, 13560-970, Brazil

    Javier Ellena

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  1. Wanessa Carvalho Pires
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Electronic supplementary material

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11010_2017_3129_MOESM1_ESM.doc

Supplementary crystallographic data for compounds [Ru(Spy)(bipy)(dppe)]PF6 (1), [Ru(Spy)(bipy)(dppp)]PF6 (2) and [Ru(Spy)(bipy)(dppf)]PF6 (4) complexes (CCDC 1427219, 1427220 and 1427801, respectively) can be obtained free of charge via http://www.cdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre (or see this session), 12 Union Road, Cambridge CB2 1 EZ, UK; fax: +44 1223 336 033; or e-mail: deposit@ccdc.com.ac.uk. Supplementary material 1 (DOC 517 kb)

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Pires, W.C., Lima, B.A.V., de Castro Pereira, F. et al. Ru(II)/diphenylphosphine/pyridine-6-thiolate complexes induce S-180 cell apoptosis through intrinsic mitochondrial pathway involving inhibition of Bcl-2 and p53/Bax activation. Mol Cell Biochem 438, 199–217 (2018). https://doi.org/10.1007/s11010-017-3129-3

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