Mitochondrial Superoxide Dismutase: A Promising Target for New Anticancer Therapies

Abstract

Compelling experimental and epidemiological evidence involves oxygen radicals in carcinogenesis, acting reactive oxygen species both as endogenous genotoxins during cell initiation and as messenger molecules in mitogenesis and in tumor promotion. Moreover, oxidants stimulate neoangiogenesis, which is a prerequisite for tumor growth. However, while several natural as well as synthetic antioxidant compounds appear to be chemopreventive in mutagenicity assays, antioxidant-based treatments for the prevention or cure of cancer have led to non-conclusive if not disappointing results. This is likely due to the fact that oxygen radicals have also a major role in the natural defences against the propagation of cancer cells, i.e. tumor cell apoptosis and immune surveillance, and mediate the beneficial cytotoxic effect of both the chemo-and radio-therapy. In recent years, the mitochondrial antioxidant enzyme, Manganous Superoxide Dismutase (MnSOD), has received a growing attention as a negative modulator of cellular apoptosis and as a survival factor for cancer cells. In fact, while overexpression of this enzyme in cancer cells decreases proliferation and tumor incidence in transgenic models, it is clear that even small amounts of this enzyme are crucial for cell resistance to inflammatory stimuli and anticancer drugs, and prevent oncogene-induced apoptosis triggered by the tumor suppressor protein p53. A previously unexpected oncogenic potential of MnSOD is also suggested by the elevated levels of this enzyme in several classes of human neoplasms, in a fashion which often correlates with the degree of their malignancy. This review focuses on the debated issue of the pro- and/or anti-tumoral effect of MnSOD, with special emphasis on recent observations suggesting that pharmacological inhibition of MnSOD may represent an effective strategy to selectively kill cancer cells and to circumvent their resistance to the commonly used anticancer treatments.

Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling

“…As our new data support the involvement of both pathways in POX-induced apoptosis, whether ROS/superoxides participate in both processes became an important question. Our strategy, similar to our previous study (Liu et al, 2005), is to hyperexpress manganese superoxide dismutase (MnSOD), an antioxidant enzyme, which decomposes superoxide radicals to hydrogen peroxide and has been reported to inhibit apoptosis induced by a variety of agents (Pani et al, 2004). Importantly, we found that MnSOD blocked the cleavage/activation not only of caspase-9 and 3, but also caspase-8, the identifying caspase of the death receptor pathway (Figure 3b).…”

The dark side of a tumor suppressor: anti-apoptotic p53

“…25 Evidently, such an antioxidant imbalance obtained by upregulation of MnSOD was also recently postulated to contribute to its potential tumor suppressive function. 88 Furthermore, similar to other pathways induced by p53, there appears to exist a reciprocal downregulation of p53 and MnSOD gene expression leading to a fine tuning of p53 activity. 90 Although this gene repression was associated with reduced promoter activity in both cases, exactly how p53 and MnSOD affect each other's expression remains to be elucidated.…”

“…Several apoptosis systems induced for example by death receptor ligands, IR, anti-cancer drugs and of course oxidative stress were efficiently counteracted by mitochondrial MnSOD, 88 another antioxidant enzyme regulated by p53. 25 Based on these and many other reports clearly validating MnSOD as a negative modulator of cellular apoptosis and hence, as a survival factor for cancer cells, it was postulated that pharmacological inhibition of MnSOD may represent an effective strategy to selectively kill cancer cells.…”

“…25 Based on these and many other reports clearly validating MnSOD as a negative modulator of cellular apoptosis and hence, as a survival factor for cancer cells, it was postulated that pharmacological inhibition of MnSOD may represent an effective strategy to selectively kill cancer cells. 88 However, elevated MnSOD protein levels were also correlated with increased oxidative stress and apoptosis induction. 25 Although contradictory, oxidative stress and apoptosis can be also caused by an antioxidant imbalance.…”

Metabolic regulation and redox activity as mechanisms for angioprevention by dietary phytochemicals

“…64 A consequence of enhanced glucose consumption is the production of reducing potential in the form of NADPH (reduced Nicotinamide Adenine Dinucleotide Phosphate) provided by upregulation of glucose-6-phosphate dehydrogenase and increased pentose phosphate pathway (PPP) activity. 69 The observation that tumor cells under constitutive oxidative stress express high levels of antioxidant enzymes 70,71 suggests that tumor cells require the upregulation of the antioxidant systems to maintain viability and proliferation. The glycolytic switch could fit an elevated requirement for fuelling the main intracellular antioxidant systems with reducing equivalents.…”