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)

Thioredoxin and thioredoxin reductase are redox proteins that have been implicated in the control of cell proliferation and transformation. We report the levels and activity of these proteins and their mRNAs in human primary tumors and tumor cell lines. Half of human primary colorectal carcinomas (5/10) examined had increased thioredoxin mRNA, of 3- to over 100-fold, compared to adjacent normal colonic mucosa from the same subject. Thioredoxin reductase protein and activity were increased an average of 2-fold in human colorectal tumors compared to normal mucosa. A number of human hematologic and solid tumor cell lines were studied and showed a 10-fold range of thioredoxin mRNA and a 23-fold range of thioredoxin reductase mRNA. Increased proliferation and hypoxia are factors that might contribute to the increased expression in solid tumors. We found that serum stimulation of growth arrested MCF-7 breast cancer cells caused a 59% increase in thioredoxin mRNA and a 62% increase in thioredoxin reductase mRNA by 24 hours. Exposure of HT-20 colon cancer cells to hypoxia resulted in a 14-fold increase in thioredoxin mRNA by 16 hours, and a transient 4-fold increase in thioredoxin reductase mRNA at 1 hour that had returned to control levels by 8 hours. Cancer cells were found to release thioredoxin into the medium at rates between 1 to 2 pmole/10(6) cells/3 hours. The rate of secretion was not, however, related to cellular-levels of thioredoxin. The results of the study show that the expression of thioredoxin and thioredoxin reductase are increased several fold in some human solid tumors compared to normal tissue. Secretion of thioredoxin, which is known to have a direct growth stimulating activity, by human tumor cells might lead to the stimulation of cancer cell growth.
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PMID:Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. 904 7

Selenium is an essential trace element, the deficiency of which is associated with an increased incidence of some human cancers. Dietary supplementation with selenium has been reported to produce a decrease in the incidence of some cancers in humans. Thioredoxin reductase (TR) is a newly discovered homodimeric selenocysteine (SeCys)-containing protein that catalyzes the NADPH-dependent reduction of the redox protein thioredoxin (Trx). Trx is overexpressed by a number of human tumors, and experimental studies have shown that Trx contributes to the growth and to the transformed phenotype of some human cancer cells. Thus, TR, by reducing Trx, could play a role in regulating the growth of normal and cancer cells. We have investigated mechanisms by which selenium, in the form of sodium selenite, added to serum-free growth medium regulates TR activity in cancer cell lines. Selenium caused a dose-dependent increase in cellular TR activity. The increase in TR activity produced by 1 microM Se compared to medium with no added selenium was: for MCF-7 breast cancer cells, 37-fold; for HT-29 colon cancer cells, 19-fold; and for A549 lung cancer cells, 8-fold. In contrast, Jurkat and HL-60 leukemia cells showed no increase in TR activity. The half-life of the time course of induction of TR in HT-29 cells after adding selenium was 10 h. The increase in TR activity was accompanied by an increase in TR protein levels up to 3-fold and an increase in the specific activity of the enzyme of 5-32-fold, depending on the cell line. Studies using 75Se showed that the amount of selenium incorporated into TR increased with increasing selenium concentration up to a ratio of 1 selenium per TR monomer. There was an increase in TR mRNA levels of 2-5-fold at 1 microM selenium and an increase in the stability of TR mRNA with a half-life for degradation of 21 h compared to 10 h in the absence of selenium. Trx mRNA and protein levels and Trx mRNA stability were not affected by selenium. The results of the study show that the increase in TR activity caused by selenium is specific and due to several effects, including an increase in the stability of TR mRNA leading to increased TR mRNA levels, an increase in TR protein, but predominantly to an increase in the specific activity of TR associated with increased incorporation of selenium into the enzyme.
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PMID:Mechanisms of the regulation of thioredoxin reductase activity in cancer cells by the chemopreventive agent selenium. 935 64

Understanding the fundamental mechanism of apoptosis is crucial to developing therapeutic strategies for controlling apoptosis in diseased tissues. We are using model systems with relevance to cancer treatment to investigate the mechanism of apoptosis. Subtraction hybridization cloning was used to identify transcripts present at higher levels in regressing vs. normal prostate; these may be important for apoptosis. One of the genes cloned from regressing prostate is also upregulated in the murine W7.2 lymphocyte cell line induced to undergo apoptosis by treatment with the synthetic glucocorticoid, dexamethasone. This gene encodes a mu class glutathione S-transferase (EC 2.5.1.18), a protein that can protect the cell against oxidative stress by repairing oxidized lipids, proteins, and DNA. Glutathione S-transferase expression does not increase with dexamethasone treatment of lymphocyte cell lines expressing nonfunctional glucocorticoid receptors or a mutation in the apoptotic pathway. Other antioxidant defenses, including catalase (EC 1.11.1.6) and superoxide dismutase (EC 1.15.1.1), decline following dexamethasone treatment of W7.2 cells. Overexpression of the bcl-2 oncogene protects these cells against dexamethasone-mediated apoptosis and prevents the decrease in antioxidant enzyme activity. These findings support the hypothesis that control of the cellular redox state is important to the mechanism of glucocorticoid-mediated lymphocyte apoptosis. Another model system we are using is tumor necrosis factor-alpha treatment of MCF-7 human breast cancer cells. Our preliminary results suggest that, in this system, activation of nuclear factor-kappa B and increased expression of manganese superoxide dismutase may afford protection from apoptosis.
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PMID:Modulation of antioxidant defenses during apoptosis. 940 33

Thioredoxin reductase is a selenocysteine containing flavoenzyme that catalyzes the NADPH dependent reduction of the redox protein thioredoxin. Thioredoxin is over-expressed by a number of human tumors. Experimental studies have shown that thioredoxin is responsible for the growth and transformed phenotype of some human cancer cells. Thus, thioredoxin reductase presents an attractive target for anticancer drug development to regulate the activity of the thioredoxin system. We have examined a series of 12 organoselenium compounds and 16 organotellurium compounds, mostly of the diaryl chalcogenide type, as inhibitors of human thioredoxin reductase and have investigated the cytotoxicity and antitumor activity of some of the compounds. The organoselenium compound Ebselen was found to be a competitive inhibitor of human thioredoxin reductase (Ki 2.8 microM), while a number of organotellurium compounds were found to be noncompetitive inhibitors (Kis 2.3 to 35.2 microM). Human glutathione reductase was not appreciably inhibited by any of the compounds, except for one dinitro organotellurium compound that caused inhibition with an IC50 of 0.5 microM and an over 20-fold selectivity compared to thioredoxin reductase. The compounds inhibited the growth of human cancer cells in culture with IC50s as low as 2 microM Some organotellurium compounds when administered daily by intraperitoneal injection to mice caused up to 50% inhibition of the growth of MCF-7 human breast cancer xenografts but the relative insolubility of the compounds was a limiting factor in their use.
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PMID:Diaryl chalcogenides as selective inhibitors of thioredoxin reductase and potential antitumor agents. 949 75

The biologic functions attributed to the nucleophosphoprotein p53 have been increasing in recent years. Some studies suggested that wild type p53 is responsible for cell cycle arrest brought about as a response to exposure of mammalian cells to DNA-damaging agents. This cell cycle arrest occurs in order for cells to repair the damaged macromolecules. Extensively damaged cells are also thought to undergo apoptosis via the p53-dependent or -independent signal transduction pathways. In this study, we investigated the ability of diaziridinylbenzoquinones to increase p53 levels in the human breast cancer cell line MCF-7. Diaziquone (AZQ), an anticancer agent, and its derivatives, diaziridinequinone (DZQ) and methyldiaziridinequinone (MeDZQ), induced p53 in a dose- and time-dependent manner as measured by the electrophoretic mobility shift assay. Wild type p53 induction by AZQ was suppressed when DT-diaphorase activity was inhibited by pretreating the cells with dicumarol. Aside from their potent alkylating activity, these agents also undergo redox cycling as evidenced by oxygen consumption and the production of reactive oxygen species (ROS). Inhibition of ROS production by the antioxidant enzyme catalase reduced AZQ- and DZQ-mediated p53 induction by about 45%. Thiotepa, a non-quinone aziridine-containing agent, and 1,4-benzoquinone (p-BQ), a redox cycling quinone, increased p53 levels. The nonalkylator oxygen-radical-generating agent menadione (MD) caused p53 induction only when MCF-7 cells were allowed to recover in drug-free media. On the basis of these data, we propose that the bioreductive activation of AZQ is a prerequisite for p53 induction. Moreover, the induction of p53 by AZQ requires both the quinone and the aziridine moieties of the AZQ molecule. Although AZQ and its analogues increased p53 levels in MCF-7 cells, p53 induction in these cells may not be responsible for the apoptosis seen upon treatment of MCF-7 cells with these agents. The uncoupling of p53 induction and apoptosis is evidenced by the generation of nucleosomal DNA laddering in aziridinequinone-treated T47D cells, a breast cancer cell line bearing a p53 mutation.
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PMID:Induction of p53 by the concerted actions of aziridine and quinone moieties of diaziquone. 954 7

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, has anticancer activity in vivo and in vitro. Doxorubicin exerts its cytotoxic effect on tumor cells mainly by two mechanisms: (a) generation of reactive oxygen species (ROS); and (b) inhibition of topoisomerase II. We studied the combined cytotoxic action of 1,25(OH)2D3 and doxorubicin on MCF-7 breast cancer cells. Pretreatement with 1,25(OH)2D3 resulted in enhanced cytotoxicity of doxorubicin. The average enhancing effect after a 72-h pretreatment with 1,25(OH)2D3 (10 nM) followed by a 24-h treatment with 1 microg/ml doxorubicin was 74+/-9% (mean +/- SE). Under these experimental conditions, 1,25(OH)2D3 on its own did not affect cell number or viability. 1,25(OH)2D3 also enhanced the cytotoxic activity of another ROS generating quinone, menadione, but did not affect cytotoxicity induced by the topoisomerase inhibitor etoposide. The antioxidant N-acetylcysteine slightly reduced the cytotoxic activity of doxorubicin but had a marked protective effect against the combined action of 1,25(OH)2D3 and doxorubicin. These results indicate that ROS are involved in the interaction between 1,25(OH)2D3 and doxorubicin. 1,25(OH)2D3 also increased doxorubicin cytotoxicity in primary cultures of rat cardiomyocytes. Treatment of MCF-7 cells with 1,25(OH)2D3 alone markedly reduced the activity, protein, and mRNA levels of the cytoplasmic antioxidant enzyme Cu/Zn superoxide dismutase, which indicated that the hormone inhibits its biosynthesis. This reduction in the antioxidant capacity of the cells could account for the synergistic interaction between 1,25(OH)2D3 and doxorubicin and may also suggest increased efficacy of 1,25(OH)2D3 or its analogues in combination with other ROS-generating anticancer therapeutic modalities.
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PMID:1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. 1002 76

Evidence from a number of studies suggests that the mechanism by which tumor necrosis factor (TNF) kills transformed cells involves oxidative stress. NAD(P)H:(quinone acceptor) oxidoreductase (NQO1) is an antioxidant enzyme with particular relevance to cancer. The MCF-7 breast cancer cell line was stably transfected with rat NQO1 cDNA to determine whether increased NQO1 activity alters sensitivity to TNF-induced apoptosis. Five clones, with a range of NQO1 enzyme activities from 5- to 50-fold greater than the MCF-7 line, and two control transfectants were examined. Northern blot hybridization analyses and reverse transcription-PCR demonstrated that the increase in NQO1 activity in the transfectants was attributable to expression from the transfected rat sequence. Based on sulforhodamine B assays for the number of viable cells, the NQO1 clones showed increased sensitivity to EO9, an indoloquinone that undergoes bioactive reduction by NQO1. Viability studies also demonstrated that the NQO1 transfectants were significantly more sensitive to TNF than the control transfectants or MCF-7 parent. This increased sensitivity could not be explained by changes in superoxide dismutase or catalase activity or to increased sensitivity to oxidative stress in general, as assessed by response to hydrogen peroxide and paraquat treatment. Using dichlorodihydrofluorescein diacetate as a probe, we found that the NQO1 transfectants had no difference in baseline level of oxidative stress compared to the control cells but did exhibit greater intracellular oxidative stress after TNF treatment. We conclude that NQO1 can affect the TNF-mediated pathway to apoptosis.
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PMID:Increased tumor necrosis factor-alpha sensitivity of MCF-7 cells transfected with NAD(P)H:quinone reductase. 1091 79

The relationship between growth and the antioxidant enzyme defence system in human MCF-7 (breast) cancer cells treated with bovine milk fat enriched with conjugated linoleic acid (CLA) was studied. Milk enriched in CLA was obtained from cows on pasture supplemented with full fat rapeseeds and full fat soyabeans (1). Cell number decreased up to 90% (p < 0.05) and lipid peroxidation increased 15-fold (p < 0.05) following incubation of MCF-7 cells for 8 days with increasing levels of milk fat yielding CLA concentrations between 16.9 and 22.6 ppm. Growth suppression and prooxidant effects of milk fat CLA were independent of the variable composition of the milk fat samples, suggesting that CLA was the active ingredient in milk fat responsible for the cytotoxic effect. Mixtures containing isomers of CLA (c9, t11-, t10, c12-, c11, t13- and minor amounts of other isomers) and linoleic acid (LA) at similar concentrations to the milk fat samples were as effective at inhibiting growth and stimulating peroxidation of MCF-7 cells as the milk fatty acids. Incubation of the cells with the c9, t11 CLA isomer (20 ppm) or the mixture of CLA isomers (20 ppm) for 8 days resulted in a 60% decrease (p < 0.05) in viability compared with untreated controls and was significantly (p < 0.05) more effective than incubation with the t10, c12 CLA isomer (20 ppm), which caused only a 15% decrease in cell numbers under similar conditions. A 25% increase (p < 0.05) in cell proliferation occurred when LA (20 ppm) alone was incubated with MCF-7 cells for 8 days. 14C-CLA was preferentially incorporated into the phospholipid fraction of the MCF-7 cell lipids in a dose-dependent manner and CLA accumulated in cell membranes more efficiently when the cells were incubated in the presence of milk fat than the c9, t11 synthetic CLA isomer. Superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) activities were induced in MCF-7 cells exposed to milk fat (containing 16.9-22.6 ppm CLA) over 8 days. The data indicate that milk fat triglyceride-bound CLA, consisting primarily of the c9, t11 isomer, was cytotoxic towards MCF-7 cells.
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PMID:Milk fat conjugated linoleic acid (CLA) inhibits growth of human mammary MCF-7 cancer cells. 1113 67

The mitochondrial antioxidant enzyme manganese-containing superoxide dismutase (MnSOD) functions as a tumor suppressor gene. Reconstitution of MnSOD expression in several human cancer cell lines leads to reversion of malignancy and induces a resistant phenotype to the cytotoxic effects of TNF and hyperthermia. The signaling pathways that underlie these phenotypic changes in MnSOD-overexpressing cells are unknown, although alterations in the activity of several redox-sensitive transcription factors, including AP-1 and NF-kappaB, have been observed. To determine the downstream signaling molecules involved in MnSOD-induced cell resistant phenotype, in the present study we analyzed the expression profile of several groups of genes related to stress response, DNA repair, and apoptosis, in a human breast cancer MCF-7 cell line overexpressing MnSOD (MCF+SOD). Of 588 genes examined, 5 (0.85%) were up-regulated (2-42-fold), and 11 (1.9%) were down-regulated (2-33-fold) in the MCF+SOD cells compared to the parental MCF-7 cells. The five up-regulated genes were MET, GADD153, CD9, alpha-catenin and plakoglobin. The genes with the most significant down-regulation included: vascular endothelial growth factor receptor 1, TNF-alpha converting enzyme, and interleukin-1beta. GADD153 (involved in the repair of DNA double strand breaks) showed a 33-fold increase in microarray analysis and these results were confirmed by RT-PCR. To further determine the specificity in MnSOD-induced gene regulation, MCF+SOD cells were stably transfected with an antisense MnSOD sequence whose expression was controlled by a tetracycline-inducible regulator. Expression of three up-regulated genes was measured after induction of antisense MnSOD expression. Interestingly, expression level of GADD153 but not MET or CD9 was reduced 24 h after antisense MnSOD induction. Together, these results suggest that reconstitution of MnSOD in tumor cells can specifically modulate the expression of down-stream effector genes. GADD153 and other elements observed in the MCF+SOD cells may play a key role in signaling the MnSOD-induced cell phenotypic change.
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PMID:Genes regulated in human breast cancer cells overexpressing manganese-containing superoxide dismutase. 1116 72

The thioredoxin system (NADPH, thioredoxin reductase/ thioredoxin) is important for cancer cell growth and inhibition of apoptosis and presents an attractive target for anticancer drug development. Thioredoxin reductase is a selenocysteine-containing flavoenzyme that catalyzes the reduction of oxidized thioredoxin. This enzyme could therefore be used for regulating the activity of the thioredoxin system. Water-soluble organotellurium compounds of the diaryl telluride, alkyl aryl telluride and dialkyl telluride type, carrying sulfopropyl groups, were found to be the most efficient tellurium-based inhibitors of thioredoxin reductase ever tested. Some of the compounds inhibited the enzyme at submicromolar levels. The compounds also inhibited the growth of MCF-7 and HT-29 human cancer cells in culture at the 5-10 microM level but their hydrophilicity seemed to restrict cellular uptake.
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PMID:Water-soluble organotellurium compounds inhibit thioredoxin reductase and the growth of human cancer cells. 1135 8


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