Title:Copper(II) Complexes with Saccharinate and Glutamine as Antitumor Agents: Cytoand Genotoxicity in Human Osteosarcoma Cells
Volume: 17
Issue: 3
Author(s): Juan F. Cadavid-Vargas, Ignacio E. Leon, Susana B. Etcheverry, Eduardo Santi, Maria H. Torre and Ana L. Di Virgilio
Affiliation:
Keywords:
Copper(II) complexes, antitumor drugs, cytotoxicity, genotoxicity, human osteosarcoma cells.
Abstract: Background: Copper has shown to be useful in disorders with an inflammation origin such as cancer [1-3].
It has previously shown that Casiopeínas® interact with DNA and promote the disruption by a mechanism related to the
increase in the level of free radicals [4-6] which confers antineoplastic potential.
Objetive: The aim of the present work was to study the antitumor effects of a series of Cu(II) complexes with
saccharinate (sac) and glutamate (gln): [Cu(sac)
2(H
2O)
4].2H
2O (Cu-sac), [Cu(gln)
2] (Cu-gln) and Na
2[Cu(sac)
2
(gln)
2].H
2O (Cu-sac-gln).
Methods: We have investigated the action of these compounds on cell viability on human osteosarcoma cells MG-63.
In particular, we pay special attention to the cyto and genotoxicity actions of these complexes and to the association to
oxidative stress.
Results: The three complexes: Cu-sac, Cu-gln and Cu-sac-gln caused a decline in cell viability. The half-maximal
inhibitory concentration in MG-63 cells for Cu-sac-gln is 170 µM, showing the strongest antiproliferative effect.
Moreover, only Cu-sac-gln caused a decrease of the mitochondrial activity from 100 µM. Our results indicate that the
copper(II) complexes studied here produce DNA damage and suggest that the rise of reactive oxygen species (ROS) is
the central mechanism action. Genotoxicity studied by the Cytokinesis-block micronucleus (MN) assay and the Single
cell gel electrophoresis (comet assay) could be observed in MG-63 cells treated with Cu-sac-gln from 100 and 50 µM,
respectively. Cu-sac and Cu-gln also induced DNA damage; however their effect was definitively weaker. The
generation of reactive oxygen species increased from 50 μM of Cu-sac-gln and Cu-sac and only from 250 µM of Cugln,
as well as a reduction of the GSH/GSSG ratio from 50 µM. When cells were treated with several concentrations of
the complexes in addition to a combination of 50 μM of vitamin C plus 50 µM of vitamin E, a total recovery in cell
survival was obtained for Cu-gln in the whole range of tested concentrations while only a partial viability recovery was
obtained from 250 µM of Cu-sac and Cu-sac-gln.
Conclusion: Overall, our results point to a differential cyto- and genotoxicity of the three copper(II) complexes and
demonstrate that the complexation with both ligands confers the most potent antitumor action in human osteosarcoma cells.
