JBIC Journal of Biological Inorganic Chemistry

, Volume 19, Issue 6, pp 787–803 | Cite as

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

  • Daniel V. Luís
  • Joana Silva
  • Ana Isabel Tomaz
  • Rodrigo F. M. de Almeida
  • Miguel Larguinho
  • Pedro V. Baptista
  • Luísa M. D. R. S. Martins
  • Telma F. S. Silva
  • Pedro M. Borralho
  • Cecília M. P. Rodrigues
  • António S. Rodrigues
  • Armando J. L. Pombeiro
  • Alexandra R. Fernandes
Original Paper

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 Kb (± 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 Kb ~4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.

Keywords

Cobalt 1,10-Phenanthroline-5,6-dione Apoptosis DNA cleavage Human serum albumin 

Supplementary material

775_2014_1110_MOESM1_ESM.pdf (1.6 mb)
Supplementary information (PDF 1633 kb)

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Copyright information

© SBIC 2014

Authors and Affiliations

  • Daniel V. Luís
    • 1
  • Joana Silva
    • 1
  • Ana Isabel Tomaz
    • 2
  • Rodrigo F. M. de Almeida
    • 3
  • Miguel Larguinho
    • 1
  • Pedro V. Baptista
    • 1
  • Luísa M. D. R. S. Martins
    • 4
    • 5
  • Telma F. S. Silva
    • 4
  • Pedro M. Borralho
    • 6
    • 7
  • Cecília M. P. Rodrigues
    • 6
    • 7
  • António S. Rodrigues
    • 8
  • Armando J. L. Pombeiro
    • 4
  • Alexandra R. Fernandes
    • 1
    • 4
    • 9
  1. 1.Departamento Ciências da Vida, Faculdade de Ciências e TecnologiaUniversidade Nova de LisboaCaparicaPortugal
  2. 2.Centro de Ciências Moleculares e Materiais, Faculdade de CiênciasUniversidade de LisboaLisbonPortugal
  3. 3.Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de CiênciasUniversidade de LisboaLisbonPortugal
  4. 4.Centro de Química Estrutural, Complexo I, Instituto Superior TécnicoUniversidade de LisboaLisbonPortugal
  5. 5.Area Departamental de Engenharia QuímicaISELLisbonPortugal
  6. 6.Departamento de Bioquímica e Biologia Humana, Faculdade de FarmáciaUniversidade de LisboaLisbonPortugal
  7. 7.Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de FarmáciaUniversidade de LisboaLisbonPortugal
  8. 8.Centro de Investigação em Genética Molecular e Humana, Departamento de Genética, Faculdade de Ciências MédicasUniversidade Nova de LisboaLisbonPortugal
  9. 9.Faculdade de EngenhariaUniversidade Lusófona de Humanidades e TecnologiasLisbonPortugal

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