Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we investigated the effects of high levels of dietary fish oil on the growth of MX-1 human mammary carcinoma and its response to mitomycin C (MC) treatment in athymic mice. We found that high levels of dietary fish oil (20% menhaden oil + 5% corn oil, w/w) compared to a control diet (5% corn oil, w/w) not only lowered the tumor growth rate, but also increased the tumor response to MC treatment. We also found that high levels of dietary fish oil significantly increased the activities of tumor xanthine oxidase and DT-diaphorase, which are proposed to be involved in the bioreductive activation of MC. Since menhaden oil is highly unsaturated, its intake caused a significant increase in the degree of fatty acid unsaturation in tumor membrane phospholipids. This alteration in tumor membrane phospholipids made the tumor more susceptible to oxidative stress, as indicated by the increased levels of both endogenous lipid peroxidation and protein oxidation after feeding the host animals the menhaden oil diet. In addition, the tumor antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPOx), and glutathione S-transferase peroxidase (GSTPx), were all significantly enhanced by feeding a diet high in fish oil. MC treatment caused further increases in tumor lipid peroxidation and protein oxidation, as well as in the activities of CAT, SOD, GPOx, and GSTPx, suggesting that MC causes oxidative stress in this tumor model which is exacerbated by feeding a diet high in menhaden oil. Thus, feeding a diet rich in menhaden oil decreased the growth of human mammary carcinoma MX-1, increased its responsiveness to MC, and increased its susceptibility to endogenous and MC-induced oxidative stress, and increased the tumor activities of two enzymes proposed to be involved in the bioactivation of MC, that is, DT-diaphorase and xanthine oxidase. These findings support a role of these two enzymes in the bioactivating of MC and indicate that the type of dietary fat may be important in tumor response to therapy.
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PMID:Dietary menhaden oil enhances mitomycin C antitumor activity toward human mammary carcinoma MX-1. 856 32

Manganese-containing superoxide dismutase (MnSOD) is an essential primary antioxidant enzyme that converts superoxide radical to hydrogen peroxide and molecular oxygen within the mitochondrial matrix. Cytosolic glutathione peroxidase (GPX) converts hydrogen peroxide into water. MnSOD is reduced in a variety of tumor types and has been proposed to be a new kind of tumor suppressor gene, but the mechanism(s) by which MnSOD suppresses malignancy is unclear. According to the enzymatic reactions catalyzed by MnSOD and cytosolic GPX, change in the cellular redox status, especially change attributable to accumulation of hydrogen peroxide or other hydroperoxides, is a possible reason to explain the suppression of tumor growth observed in MnSOD-overexpressing cells. To test this possible mechanism, we transfected human cytosolic GPX cDNA into human glioma cells overexpressing MnSOD. The results showed that GPX overexpression not only reversed the tumor cell growth inhibition caused by MnSOD overexpression but also altered the cellular contents of total glutathione, reduced glutathione, oxidized glutathione, and intracellular reactive oxygen species. Overexpression of GPX also inhibited degradation of the inhibitory subunit alpha of nuclear factor-KB. These results suggest that hydrogen peroxide or other hydroperoxides appear to be key reactants in the tumor suppression by MnSOD overexpression, and growth inhibition correlates with the intracellular redox status. This work suggests that manipulations that inhibit peroxide removal should enhance the tumor suppressive effect of MnSOD overexpression.
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PMID:The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase. 1091 71

Copper zinc superoxide dismutase (CuZnSOD) is an essential primary antioxidant enzyme that converts superoxide radical to hydrogen peroxide and molecular oxygen in the cytoplasm. Cytosolic glutathione peroxidase (GPx) converts hydrogen peroxide into water. The overall goal of the present study was to explore the possible role of the antioxidant enzyme CuZnSOD in expression of the malignant phenotype. We hypothesized that overexpression of CuZnSOD would lead to the suppression of at least part of the human malignant phenotype. To test this hypothesis, human CuZnSOD cDNA was transfected into U118-9 human malignant glioma cells. CuZnSOD activity levels increased 1.5-, 2.0-, 2.6-, and 3.5-fold, respectively, in four table transfected cell lines compared with wild type and vector controls. Overexpression of CuZnSOD altered cellular antioxidant enzyme profiles, including those of manganese superoxide dismutase, catalase, and GPx. The transfected clone with the highest CuZnSOD:GPx ratio (3.5) showed a 42% inhibition of tumor cell growth in vitro. The decreased rate of tumor cell growth in vitro was strongly correlated with the enzyme activity ratio of CuZnSOD:GPx. Glioma cells that stably overexpressed CuZnSOD demonstrated additional suppressive effects on the malignant phenotype when compared with the parental cells and vector controls. These cells showed decreased plating efficiency, elongated cell population doubling time, lower clonogenic fraction in soft agar, and, more significantly, inhibition of tumor formation in nude mice. This work suggested that CuZnSOD is a new tumor suppressor gene. Increased intracellular ROS levels were found in cells with high activity ratios of CuZnSOD:GPx. Change in the cellular redox status, especially change attributable to the accumulation of hydrogen peroxide or other hydroperoxides, is a possible reason to explain the suppression of tumor growth observed in CuZnSOD-overexpressing cells.
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PMID:Overexpression of copper zinc superoxide dismutase suppresses human glioma cell growth. 1186 5

Chronic pancreatitis, K-ras oncogene mutations, and the subsequent generation of reactive oxygen species (ROS) appear to be linked to pancreatic cancer. ROS have also been suggested to be mitogenic and capable of stimulating cell proliferation. Cells contain antioxidant enzymes to regulate steady state levels of ROS produced by products of metabolism. The aims of our study were to determine antioxidant enzyme activity in pancreatic cancer cells and correlate enzyme activity with tumor growth, as well as determine whether tumor cell growth could be altered with antioxidant gene transfection. Western blots, enzyme activity, and enzyme activity gels were performed for manganese superoxide dismutase (MnSOD), copper/zinc, catalase, and glutathione peroxidase in normal human pancreas and in the human pancreatic cancer cell lines BxPC-3, Capan-1, MIA PaCa-2, and AsPC-1. Cell population doubling times were determined and correlated with antioxidant enzyme activity. MnSOD was overexpressed in MIA PaCa-2 using an adenoviral vector, and the effect on cell growth was determined. The cell pancreatic cancer lines BxPC-3, MIA PaCa-2, and AsPC-1 had decreased levels of MnSOD immunoreactive protein as well as activity and decreases in MnSOD levels correlated well with increased rates of tumor cell proliferation as determined by cell doubling time. No correlation could be found between cell growth and levels of copper/zinc superoxide dismutase, catalase, or glutathione peroxidase. Enforced expression of MnSOD by adenovirus transfection in the rapid growing cell line MIA PaCa-2 increased MnSOD immunoreactivity and MnSOD activity and decreased growth rate. Overexpression of MnSOD may be effective in growth suppression of pancreatic cancer.
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PMID:The role of manganese superoxide dismutase in the growth of pancreatic adenocarcinoma. 1264 90

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.
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PMID:Mitochondrial superoxide dismutase: a promising target for new anticancer therapies. 1513 21

Thioredoxin reductase (TRX) is a selenoprotein that reduces oxidized protein substrates in an NADPH-dependent process (cf. Fig. 1). The thioredoxins (TX) are a family of small redox active proteins that undergo reversible oxidation/reduction and help to maintain the redox state of cells. TX serves as a cofactor in many TRX-catalyzed reductions in a manner similar to glutathione (GSH) in thioltransferase reactions. For example, TX is a cofactor in protein disulfide reduction and DNA synthesis, but independently, it inhibits apoptosis, stimulates cell proliferation and angiogenesis, and increases transcription factor activity. The role of the TRX/TX system is limited by its reducing capacity as well as the additional supply of electrons in the form of NADPH provided by hexose monophosphate shunt (HMPS). TX is limited by the reduction capacity of its vicinal sulfhydryls and needs a source of electrons from the HMPS and TRX- coupled system to reduce disulfides. Oxidized TX is reduced by TRX and NADPH. Several lines of evidence suggest that the coupled HMPS/TRX/TX system represents an important target for cancer therapy. TX overexpression has been reported in several malignancies and may be associated with aggressive tumor growth and poor survival. In some cells, TX is an important factor in conferring resistance to chemotherapy and in stimulating production of hypoxia-inducible factor (HIF-1). Several inhibitors of the TRX/TX system have been evaluated in experimental cancer models: these include HMPS inhibitors, carbohydrate analogues, NADP synthesis blockers, vicinal thiol reactants, cisplatin, and TRX inhibitors. More recently, the targeted anti-cancer agent motexafin gadolinium has been identified. Motexafin gadolinium is a redox mediator that selectively localizes to cancer cells, and reacts with reducing metabolites and vicinal thiols to generate reactive oxygen species that ultimately block the TRX enzyme as well as the analogous glutaredoxin activity. In cell and animal models, motexafin gadolinium is directly cytotoxic to various tumor cells and enhances the activity of radiation therapy and chemotherapy. This drug is now in a broad range of clinical trials investigating its therapeutic potential when used as a single agent or in combination with either chemotherapy or radiation therapy. Promising clinical activity has been reported in a clinical trial with motexafin gadolinium and whole brain radiation therapy for treatment of brain metastases from solid tumors. These findings suggest that the TRX/TX system may represent an attractive target for development of new cancer therapeutics.
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PMID:The thioredoxin reductase/thioredoxin system: novel redox targets for cancer therapy. 1568 6

Induced chemoluminescence was used for 30 days to measure lipids peroxidation in transplantable sarcoma-45 homogenates in 83 noninbred male rats. It was found that tumor/body interaction can be interpreted in terms of free-radical oxidation processes taking place in tumor tissue. In the middle of the experiment, the kinetics of chemoluminescence soared up which was accompanied by slight increase in tumor mass. Later on, tumor growth involved a rise in antioxidant enzyme levels which is supposedly accounted for by the expression of the genes responsible for the rate of antioxidant reactions in general. That increase resulted in uncontrollable growth of tumor.
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PMID:[Dynamics of free-radical oxidation processes in transplantable sarcoma-45 as indicator of tumor and body interaction]. 1622 7

Both selenium and green tea have been shown to have potential antitumor effects. Here we have investigated the anticarcinogenic effect of the selenium-enriched green tea extract (Se-TE) in a Kunming mice model transplanted with human hepatoma cells HepG2. Mice were assigned to 8 groups consisting of 10 mice each after tumor cell inoculation. The control group received only water, whereas the remaining groups received regular green tea extract (RT), Se-TE which was produced by fertilization with selenite on tea leaves, selenite, and RT + selenite. After the mice were fed intragastrically with these agents for 8 days, tumor growth in RT-, Se-TE-, and selenite-fed mice was significantly suppressed, compared with that in control mice (P < 0.001). Supplementation with Se-TEs and selenite was able to elevate mice blood and liver Se concentrations, but did not significantly enhance selenoprotein glutathione peroxidase and other antioxidant enzyme superoxide dismutase activity in mice blood and liver. These results suggest that the antitumor function of Se-TEs may be attributed to the oxidative stress induced by selenium and green tea components in a suitable selenium supplementation pathway.
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PMID:Anticarcinogenic activity of selenium-enriched green tea extracts in vivo. 1754 12

Manganese superoxide dismutase (MnSOD) is the only primary antioxidant enzyme in mitochondria that scavenges superoxide radicals. Overexpressing MnSOD in cancer cells by cDNA transfection suppresses tumor formation and reverses malignant growth. In this study, we examined the effect of recombinant human manganese superoxide dismutase (rhMnSOD) alone and in combination with adriamycin (ADR) against solid tumors of sarcoma 180 in Institute of Cancer Research (ICR) mice. Administration of rhMnSOD alone and in combination with ADR significantly inhibited tumor growth in a dose-dependent manner. The use of rhMnSOD in combination with ADR enhanced ADR's anti-tumor potency without increasing toxicity. Histopathological examination provided evidence of the anti-tumor effect. In addition, we found lymphocyte infiltration of the tumors, with an increase in both CD4- and CD8-positive cells in the treated tumors. The expression of CD4 and CD8 was up-regulated with increasing dose of rhMnSOD, and the combination treatment with ADR further enhanced this up-regulation. Collectively, these data indicate that rhMnSOD may exhibit an anti-tumor effect by stimulating the immune system and promoting the recruitment of lymphocytes into the tumor to kill tumor cells. Thus MnSOD may constitute a potential new therapeutic agent to be exploited as an adjuvant in cancer therapy.
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PMID:Enhanced anti-tumor effects achieved in a murine tumor model using combination therapy of recombinant human manganese superoxide dismutase and adriamycin. 1841 39

Cancer cells produce high amounts of reactive oxygen species (ROS) and evade apoptosis. Hydroperoxides support proliferation, invasion, migration and angiogenesis, but at higher levels induce apoptosis, thus being pro- and anti-carcinogenic. Accordingly, glutathione peroxidases (GPxs) regulating hydroperoxide levels might have dual roles too. GPx1, clearly an antioxidant enzyme, is down-regulated in many cancer cells. Its main role would be prevention of cancer initiation by ROS-mediated DNA damage. GPx2 is up-regulated in cancer cells. GPx1/GPx2 double knockout mice develop colitis and intestinal cancer. However, GPx2 knockdown cancer cells grow better in vitro and in vivo probably reflecting the physiological role of GPx2 in intestinal mucosa homeostasis. GPx2 counteracts COX-2 expression and PGE(2) production, which explains its potential to inhibit migration and invasion of cultured cancer cells. Overexpression of GPx3 inhibits tumor growth and metastasis. GPx4 is decreased in cancer tissues. GPx4-overexpressing cancer cells have low COX-2 activity and tumors derived therefrom are smaller than from control cells and do not metastasize. Collectively, GPxs prevent cancer initiation by removing hydroperoxides. GPx4 inhibits but GPx2 supports growth of established tumors. Metastasis, but also apoptosis, is inhibited by all GPxs. GPx-mediated regulation of COX/LOX activities may be relevant to early stages of inflammation-mediated carcinogenesis.
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PMID:Glutathione peroxidases in different stages of carcinogenesis. 1928 49


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