Induction of oxidative damage by copper-based antineoplastic drugs (Casiopeínas).
OBJECTIVE
The aim of the present study is to determine in HeLa cells and in human lymphocytes, by an easy and fast method, the induction of oxidative damage to plasma membrane lipids and nuclear DNA by Casiopeínas, which are recently synthesized coordination complexes that have been considered as a promising chemotherapeutic alternative for the treatment of cancer, since they have shown cytotoxicity and genotoxicity in several cancer cell lines and xenotransplanted tumours. The presence of an oxidized copper atom in their structure strongly suggests that their mode of action seems to be related to reactive oxygen species (ROS) generation after copper atom reduction through the Fenton and Haber-Weiss system.


METHODS
Lipid peroxidation was evaluated as thiobarbituric acid reactive malondialdehyde, cytotoxicity by the fluorescein diacetate/ethidium bromide stain and genotoxicity as DNA fragmentation by the comet assay. Cells were treated with ten different Casiopeínas in a concentration range higher than their IC(50) (10-100 microM), both oxidized and reduced in the presence of ascorbic acid.


RESULTS
In almost all the cases, copper reduction enhanced cytotoxicity but, unlike copper nitrate used as positive control, none of them induced appreciable lipid peroxidation. Three Casiopeínas: Cas Igly, Cas-III-H-a and Cas-III-E-a, showed low, moderate and high rates of genotoxicity, respectively, and this effect was enhanced upon addition of ascorbic acid.


CONCLUSIONS
These results suggest that ROS generation might be the cause of cytotoxicity, which seems to be related to initial genetic damage rather than to lipid peroxidation. HeLa cells showed to be more sensitive than normal cells.
Alemón-Medina
Radamés
R
Departamento de Biología, Instituto Nacional de Investigaciones Nucleares (ININ), Carretera México-Toluca S/N, La Marquesa, Ocoyoacac, 52750 Mexico, Mexico.
Breña-Valle
Matilde
M
Muñoz-Sánchez
José Luis
JL
Gracia-Mora
María Isabel
MI
Ruiz-Azuara
Lena
L
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species
D000970:Antineoplastic Agents; D009566:Nitrates; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D003300:Copper; C516433:copper(II) nitrate