Article

Casiopeína IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells

Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
Toxicology (Impact Factor: 3.62). 12/2009; 268(3):176-83. DOI: 10.1016/j.tox.2009.12.010
Source: PubMed

ABSTRACT

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.

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    • "HeLa cells treated with Cas IIgly demonstrated a significant release of apoptogenic factors such as cytochrome c and Bax, leading to caspase activation and subsequent cellular death by apoptosis (Mejia and Ruiz-Azuara 2008; Valencia-Cruz et al. 2013). Furthermore , previous findings have suggested that the Cas redox cycle promotes reactive oxygen species (ROS) production and intracellular glutathione (GSH) depletion, increasing levels of mitochondrial ROS and, consequently inducing mitochondrial dysfunction and apoptosis (Kachadourian et al. 2010). In this regard, Cas mitochondrial oxidative damages can be associated with the cardiotoxicity caused by doxorubicin (Doxo) (Zhou et al. 2001). "
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    • "In previous studies, another copper compound (Cas IIgly [Cu(4,7-dimethyl-1,10-phenanthroline)(glycine)(H2O)]NO3) was shown to induce a dramatic drop in intracellular levels of reduced glutathione (GSH) in human lung cancer H157 and in A547 cells. GSH was used as a source of electrons to catalyze the Fenton reaction leading to ROS formation and cell death [13]. ROS are regulators of mitogen-activated protein kinase (MAPKS), a family of serine/threonine kinases, which mediates intracellular signal transduction in response to different physiological stimuli and stressing conditions [14,15]. "
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    • "Such species may interact directly with DNA, yet results from experiments done elsewhere point towards other potential cell targets such as membrane lipids (Alemon-Medina et al., 2007) and mitochondria (Marin et al., 2003). Recently, Kachadourian et al. (2010) demonstrated that CasII-gly dramatically drops the intracellular levels of GSH in human lung cancer cells, and is able to use GSH as a source of electrons to catalyze the Fenton-like reaction , causing an over-production in the mitochondria of reactive oxygen species and a depolarization of the mitochondrial membrane . These suggest that CasII-gly initiates multiple possible sources of ROS over-production leading to mitochondrial dysfunction and cell death. "
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