The influence of oxo-bridged binuclear gold(III) complexes on Na/K-ATPase activity: a joint experimental and theoretical approach

  • Aleksandra M. Bondžić
  • Mirjana B. Čolović
  • Goran V. Janjić
  • Božidarka Zarić
  • Sandra Petrović
  • Danijela Z. Krstić
  • Tiziano Marzo
  • Luigi Messori
  • Vesna M. Vasić
Original Paper

DOI: 10.1007/s00775-017-1460-5

Cite this article as:
Bondžić, A.M., Čolović, M.B., Janjić, G.V. et al. J Biol Inorg Chem (2017). doi:10.1007/s00775-017-1460-5
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Abstract

The in vitro effects of oxo-bridged binuclear gold(III) complexes, i.e., [(bipy2Me)2Au2(μ-O)2][PF6]2 (Auoxo6), Au2[(bipydmb-H)2(μ-O)][PF6] (Au2bipyC) and [Au2(phen2Me)2(μ-O)2](PF6)2 (Au2phen) on Na/K-ATPase, purified from the porcine cerebral cortex, were investigated. All three studied gold complexes inhibited the enzyme activity in a concentration-dependent manner achieving IC50 values in the low micromolar range. Kinetic analysis suggested an uncompetitive mode of inhibition for Auoxo6 and Au2bipyC, and a mixed type one for Au2phen. Docking studies indicated that the inhibitory actions of all tested complexes are related to E2-P enzyme conformation binding to ion channel and intracellular part between N and P sub-domain. In addition, Au2phen was able to inhibit the enzyme by interacting with its extracellular part as well. Toxic effects of the gold(III) complexes were evaluated in vitro by following lactate dehydrogenase activity in rat brain synaptosomes and incidence of micronuclei and cytokinesis-block proliferation index in cultivated human lymphocytes. All investigated complexes turned out to induce cytogenetic damage consisting of a significant decrease in cell proliferation and an increase in micronuclei in a dose-dependent manner. On the other hand, lactate dehydrogenase activity, an indicator of membrane integrity/viability, was not affected by Auoxo6 and Au2bipyC, while Au2phen slightly modified its activity.

Graphical Abstract

Keywords

Binuclear gold(III) complexes Na/K-ATPase Inhibition Docking studies Cytotoxicity Genotoxicity 

Abbreviations

REA

Relative enzyme activity

ATP

Adenosine triphosphate

NADH

Nicotinamide adenine dinucleotide reduced

LDH

Lactate dehydrogenase

CBPI

Cytokinesis-block proliferation index

MN

Incidence of micronuclei

Supplementary material

775_2017_1460_MOESM1_ESM.pdf (428 kb)
Supplementary material 1 (PDF 428 kb)

Copyright information

© SBIC 2017

Authors and Affiliations

  • Aleksandra M. Bondžić
    • 1
  • Mirjana B. Čolović
    • 1
  • Goran V. Janjić
    • 2
  • Božidarka Zarić
    • 2
  • Sandra Petrović
    • 1
  • Danijela Z. Krstić
    • 4
  • Tiziano Marzo
    • 3
    • 5
  • Luigi Messori
    • 3
  • Vesna M. Vasić
    • 1
  1. 1.Department of Physical Chemistry, Vinča Institute of Nuclear SciencesUniversity of BelgradeBelgradeSerbia
  2. 2.Institute of Chemistry, Metallurgy and TechnologyUniversity of BelgradeBelgradeSerbia
  3. 3.Department of ChemistryUniversity of FlorenceSesto FiorentinoItaly
  4. 4.Institute of Medical Chemistry, Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  5. 5.Department of Chemistry and Industrial ChemistryUniversity of PisaPisaItaly

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