Casiopeínas are a series of mixed chelate
copper complexes that are being evaluated as
anticancer agents. Their effects in the cell include oxidative damage and
mitochondrial dysfunction, yet the molecular mechanisms leading to such effects remain unclear. We tested whether [Cu(4,7-dimethyl-
phenanthroline)(glycinate)]NO(3) (Casiopeína IIgly or
Cas IIgly) could alter cellular
glutathione (GSH) levels by redox cycling with GSH to generate ROS and cellular oxidative stress.
Cas IIgly induced a dramatic drop in intracellular levels of GSH in human
lung cancer H157 and A549 cells, and is able to use GSH as source of electrons to catalyze the Fenton reaction. In both cell lines, the toxicity of
Cas IIgly (2.5-5 microM) was potentiated by the GSH synthesis inhibitor l-
buthionine sulfoximine (BSO) and diminished by the catalytic
antioxidant manganese(III) meso-tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin (MnTDE-1,3-IP(5+)), thus supporting an important role for oxidative stress.
Cas IIgly also caused an over-production of
reactive oxygen species (ROS) in the mitochondria and a depolarization of the mitochondrial membrane. Moreover,
Cas IIgly produced
mitochondrial DNA damage that resulted in an imbalance of the expression of the
apoproteins of the mitochondrial respiratory chain, which also can contribute to increased ROS production. These results suggest that
Cas IIgly initiates multiple possible sources of ROS over-production leading to
mitochondrial dysfunction and cell death.