title: Copper(II) Complexes with Saccharinate and Glutamine as Antitumor Agents: Cytoand Genotoxicity in 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(H2O)4].2H2O (Cu-sac), [Cu(gln)2] (Cu-gln) and Na2[Cu(sac)2 (gln)2].H2O (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CEQUINOR (Centro de Quimica Inorganica), CONICET- Facultad de Ciencias Exactas, UNLP. 47 y 115 (1900) La Plata, Argentina.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Cadavid-Vargas
authors.affiliation: CEQUINOR (Centro de Quimica Inorganica), CONICET- Facultad de Ciencias Exactas, UNLP. 47 y 115 (1900) La Plata, Argentina.
authors.forename: Ignacio E
authors.initials: IE
authors.lastname: Leon
authors.affiliation: CEQUINOR (Centro de Quimica Inorganica), CONICET- Facultad de Ciencias Exactas, UNLP. 47 y 115 (1900) La Plata, Argentina.
authors.forename: Susana B
authors.initials: SB
authors.lastname: Etcheverry
authors.affiliation: Quimica Inorganica, Facultad de Quimica, Universidad de la Republica, Gral. Flores 2124, Montevideo, Uruguay.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Santi
authors.affiliation: Quimica Inorganica, Facultad de Quimica, Universidad de la Republica, Gral. Flores 2124, Montevideo, Uruguay.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Torre
authors.affiliation: CEQUINOR and Catedra de Bioquimica Patologica, Facultad de Ciencias Exactas, UNLP. 47 y 115 (1900) La Plata, Argentina.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Di Virgilio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005973:Glutamine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D012439:Saccharin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D005973:Glutamine; D003300:Copper; D012439:Saccharin
keywords: Copper(II) complexes; antitumor drugs; cytotoxicity; genotoxicity; human osteosarcoma cells