Sulphur-containing non enzymatic antioxidants: Therapeutic tools against cancer

Department of Biologia Molecular y Bioquimica, Facultad de Ciencias, Campus de Teatinos, Universidad de Malaga, Malaga, Spain.
Frontiers in bioscience (Scholar edition) 01/2012; 4(2):722-48.
Source: PubMed

ABSTRACT The prevention of oxidation is an essential process in all cells, as decreased antioxidant protection may lead to cytotoxicity, mutagenicity and carcinogenicity. The mechanisms by which oxidative stress contributes to carcinogenesis include modulation of gene expression and induction of genetic modifications. Cellular methylation and antioxidant metabolism are linked by the transsulfuration pathway, which converts the methionine cycle intermediate, homocysteine, to cysteine, the limiting reagent in glutathione synthesis. Taurine can protect cells from oxidant-induced injury scavenging strong oxidant and cytotoxic agents, and lipoic acid can regenerate glutathione. N-acetylcysteine has anticancer properties such as counteractions against mutagens and prevention of tumor progression. The oxidizing agents react with the thiol group of these non enzymatic antioxidants determining cellular redox potential, and modulating several biological events, since different redox-sensitive molecules are involved in many cell responses such as proliferation, growth arrest, and death. The high metabolic activity characteristic of cancer cells often upregulates oxidative stress protection mechanisms. In fact, glutathione depletion is an early hallmark observed in apoptosis and it has been demonstrated as a common feature of cancer.

Download full-text


Available from: Jose Mates, Aug 06, 2014
60 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study investigated the effects of breast tumors on the blood and tissue distribution of essential trace mineral selenium (Se), and oxidative stress status of mice. Female 10-week-old BALB/cByJNarl mice were randomly assigned into control (CNL) and breast tumor-bearing (TB) groups. TB mice were injected subcutaneously into the right hind thigh with 5 × 106 EMT6 mouse mammary tumor cells. After 22 days, we measured Se concentrations, Se-dependent glutathione peroxidase (GPx) activities, and malondialdehyde (MDA) products (indicator of oxidative stress) in plasma, various tissues, and plasma vascular endothelial growth factor (VEGF) concentrations. There were no significant differences in body weights and daily intake between both groups. Compared with the CNL group, TB mice have decreases in plasma Se concentrations and GPx activities, as well as higher plasma VEGF and MDA concentrations. Plasma Se concentrations were also negatively correlated with plasma MDA and VEGF concentrations. Furthermore, tissue Se concentrations and GPx activities in TB animals were lower; whereas the MDA concentrations higher in various tissues including liver, kidney, brain, lung, spleen, and thymic tissues. In conclusion, disruption of Se homeostasis critically reflects oxidative stress in target tissues, thus may increase the risk for progression of breast cancer and metastasis.
    Nutrients 02/2013; 5(2):594-607. DOI:10.3390/nu5020594 · 3.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFkB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish "metabolic parasites", like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted "antibiotics" to selectively starve cancer cells. Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon Stephen Paget.
    Cell cycle (Georgetown, Tex.) 07/2013; 12(16). DOI:10.4161/cc.25510 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Redox imbalance is a primary cause for endothelial dysfunction (ED). Under oxidant stress, many critical proteins regulating endothelial function undergo oxidative modifications that lead to ED. Cellular levels of GSH, the primary reducing source in cells, can significantly regulate cell function via reversible protein thiol modification. N-Acetyl cysteine (NAC), a precursor for GSH biosynthesis, is beneficial for many vascular diseases; however, the detailed mechanism of these benefits is still not clear. From HPLC analysis, NAC significantly increases both cellular GSH and BH4 levels. Immunoblotting of eNOS and DUSP4, a dual-specificity phosphatase with a cysteine as its active residue, revealed that both enzymes are up-regulated by NAC. EPR spin-trapping further demonstrated that NAC enhances NO generation from cells. Long-term exposure to Cd(2+) contributes to DUSP4 degradation and the uncontrolled activation of p38 and ERK1/2, leading to apoptosis. Treatment with NAC prevents DUSP4 degradation and protects cells against Cd(2+)-induced apoptosis. Moreover, the increased DUSP4 expression can redox regulate p38 and ERK1/2 pathways from hyper-activation, providing a survival mechanism against the toxicity of Cd(2+). DUSP4 gene knockdown further supports the hypothesis that DUSP4 is an antioxidant gene, critical in the modulation of eNOS translation, and thus protects against Cd(2+)-induced stress. Depletion of intracellular GSH by BSO makes cells more susceptible to Cd(2+)-induced apoptosis. Pre-treatment with NAC prevents p38 over-activation and thus protects the endothelium from this oxidative stress. Therefore, the identification of DUSP4 activation by NAC provides a novel target for future drug design.
    Free Radical Biology and Medicine 06/2014; 74. DOI:10.1016/j.freeradbiomed.2014.06.016 · 5.74 Impact Factor
Show more