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Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies

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Abstract

The very high antiproliferative activity of [Co(Cl)(H2O)(phendione)2][BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 μM) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that [Co(Cl)(phendione)2(H2O)][BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 % at 1 μM, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K b (± standard error of the mean) of (3.48 ± 0.03) × 105 M−1 and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K b ~4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.

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Acknowledgments

Part of this work was financed by Portuguese national funds through FCT, the Portuguese Foundation for Science and Technology, within the scope of projects PTDC/QuiQui/101187/2008, PEst-OE/QUI/UI0612/2013, and PEst-OE/QUI/UI0536/2013, as well as Ciência2008 and Investigator FCT-POPH initiatives. We thank Ana C. Silva for fruitful discussions.

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Authors and Affiliations

  1. Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal

    Daniel V. Luís, Joana Silva, Miguel Larguinho, Pedro V. Baptista & Alexandra R. Fernandes

  2. Centro de Ciências Moleculares e Materiais, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016, Lisbon, Portugal

    Ana Isabel Tomaz

  3. Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisbon, Portugal

    Rodrigo F. M. de Almeida

  4. Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal

    Luísa M. D. R. S. Martins, Telma F. S. Silva, Armando J. L. Pombeiro & Alexandra R. Fernandes

  5. Area Departamental de Engenharia Química, ISEL, Lisbon, Portugal

    Luísa M. D. R. S. Martins

  6. Departamento de Bioquímica e Biologia Humana, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal

    Pedro M. Borralho & Cecília M. P. Rodrigues

  7. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal

    Pedro M. Borralho & Cecília M. P. Rodrigues

  8. Centro de Investigação em Genética Molecular e Humana, Departamento de Genética, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal

    António S. Rodrigues

  9. Faculdade de Engenharia, Universidade Lusófona de Humanidades e Tecnologias, Lisbon, Portugal

    Alexandra R. Fernandes

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  1. Daniel V. Luís
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Correspondence to Alexandra R. Fernandes.

Additional information

D.V. Luís and J. Silva contributed equally to this work.

Electronic supplementary material

Spectroscopic data for doxorubicin–DNA and complex–HSA interactions and restriction analysis of base-specific complex–DNA interaction, comet assay, T4 DNA ligation assay, and viability assay on a nontumor human cell line.

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Luís, D.V., Silva, J., Tomaz, A.I. et al. Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies. J Biol Inorg Chem 19, 787–803 (2014). https://doi.org/10.1007/s00775-014-1110-0

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