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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antioxidant defence plays a crucial role in rapidly growing and multiplying organisms, including parasites and tumor cells. Apart from reactive oxygen species (ROS) produced in endogenous reactions, parasites are usually exposed to high ROS concentrations imposed by the host immune system. The glutathione and thioredoxin systems represent the two major antioxidant defence lines in most eukaryotes and prokaryotes. Trypanosomatids, however, are characterized by their unique trypanothione system. These systems are NADPH-dependent and based on the catalytic activity of the flavoenzymes glutathione reductase, trypanothione reductase and thioredoxin reductase (TrxR), respectively. TrxR reduces the 12-kDa protein thioredoxin (Trx), which in turn provides elcctrons to ribonucleotide reductase, thioredoxin peroxidases (TPxs), certain transcription factors and other target molecules. Comparing the thioredoxin systems of different parasites and their respective host cells enhances our understanding of parasite biology and evolution, of parasite-host interactions and mechanisms of drug resistance. It furthermore opens avenues for the development of novel antiparasitic compounds. Here we review the current knowledge on the Trx systems of eukaryotic parasites, finally focusing on the malarial parasite Plasmodium falciparum.
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PMID:The thioredoxin system of Plasmodium falciparum and other parasites. 1216 15

The IFN and retinoic acid (RA) combination suppresses cell growth by inducing apoptosis in the cultured tumor cells. Using a genetic technique, we have isolated several "genes associated with retinoid-IFN-induced mortality" (GRIM) that participate in this death pathway. One such gene, GRIM-12, encodes the redox enzyme thioredoxin reductase (TR). Antisense-mediated inhibition of TR abrogates cell death. To test the in vivo relevance of TR for growth suppression, we have conducted the following study. A wild-type TR or a catalytically defective mutant were expressed in MCF-7 breast carcinoma cells and transplanted into athymic nude mice. These mice were treated with IFN-beta and all-trans RA combination. Tumors expressing the vector or wild-type TR were readily suppressed by the IFN/RA combination. In contrast, the tumors bearing a mutant TR were resistant to regression. We further show that markers of apoptosis are stimulated in the regressing tumors. These studies show a prominent role for TR in tumor-growth suppression.
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PMID:Thioredoxin reductase plays a critical role in IFN retinoid-mediated tumor-growth control in vivo. 1237 91

The cellular defense system (including glutathione, glutathione-related enzymes, antioxidant and redox enzymes) plays a crucial role in cell survival and growth in aerobic organisms. To understand its physiological role in tumor cells, the glutathione content and related enzyme activities in the human normal hepatic cell line, Chang and human hepatoma cell line, HepG2, were systematically measured and compared. Superoxide dismutase, catalase, and glutathione peroxidase activities are 2.8-, 4.3-, and 2.9-fold higher in HepG2 cells than in Chang cells. Total glutathione content is also about 1.4-fold higher in HepG2, which is supported by significant increases in gamma-glutamylcysteine synthetase and glutathione synthetase activities. Two other glutathione-related enzymes, glutathione reductase and gamma-glutamyltranspeptidase, are upregulated in HepG2 cells. However, thioredoxin reductase and glutathione S-transferase activities are significantly lower in HepG2 cells. These results propose that defense-related enzymes are largely modulated in tumor cells, which might be linked to their growth and maintenance.
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PMID:Activities of antioxidant and redox enzymes in human normal hepatic and hepatoma cell lines. 1244 6

Besides scavenging free radicals, antioxidants inhibit signaling enzymes such as protein kinase C (PKC) that play a crucial role in tumor promotion. By having different oxidation susceptible regions, PKC can respond to both oxidant tumor promoters and cancer-preventive antioxidants to elicit opposite cellular responses. Oxidant tumor promoters activate PKC by reacting with zinc-thiolates present within the regulatory domain. In contrast, the oxidized forms of some cancer-preventive agents, such as polyphenolics (ellagic acid, 4-hydroxytamoxifen and curcumin) and selenocompounds, can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. This brings an efficient counteractive mechanism to block the signal transduction induced by tumor promoters at the first step itself. Because prostate cancer prevention clinical trials in large human population are under way, we have focused more on understanding the cancer-preventive mechanism of selenium. Methylselenol, the postulated cancer-preventive metabolite, has no direct effect on PKC activity. However, methylseleninic acid, locally generated by the reaction of membrane methylselenol with PKC-bound tumor-promoting fatty acid hydroperoxides, selectively inactivates PKC. This mechanism clarifies how the volatile methylselenol that is present in a low concentration induces the inactivation of PKC selectively in the promoting precancer cells. Selenoprotein thioredoxin reductase reverses selenium-induced inactivation of PKC, suggesting that selenoproteins may serve as a safeguard against the toxicity induced by selenometabolites. Moreover, this also explains how a resistance to selenium develops in advanced malignant cells. The redox-mediated inactivation of PKC may, at least in part, be responsible for the antioxidant-induced inhibition of tumor promotion and cell growth, as well as for the induction of cell death.
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PMID:Antioxidant regulation of protein kinase C in cancer prevention. 1246 31

The thioredoxins are small ubiquitous redox proteins with the conserved redox catalytic sequence-Trp-Cys-Gly-Pro-Cys-Lys, where the Cys residues undergo reversible NADPH dependent reduction by selenocysteine containing flavoprotein thioredoxin reductases. Thioredoxin expression is increased in several human primary cancers including lung, colon, cervix, liver, pancreatic, colorectal and squamous cell cancer. The thioredoxin/thioredoxin reductase pathway therefore provides an attractive target for cancer drug development. Organotellurium steroid, lipid, amino acid, nucleic base, and polyamine inhibitors were synthesized on the basis that they might be selectively or differentially incorporated into tumor cells. Some of the newly prepared classes of tellurium-based inhibitors (lipid-like compounds 3b and 3e, amino acid derivative 5b, nucleic base derivative 8b, and polyamine derivatives 14a and 14b) inhibited TrxR/Trx and cancer cell growth in culture with IC(50) values in the low micromolar range.
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PMID:Thioredoxin reductase and cancer cell growth inhibition by organotellurium compounds that could be selectively incorporated into tumor cells. 1460 73

Thioredoxin (Trx) inhibited human HMEC-1 dermal microvascular endothelial cell capillary tubule forming capacity in a Matrigel based assay in vitro. Inhibition of capillary tubule formation was Trx catalytic site and thioredoxin reductase (TrxR) dependent, mediated at the Matrigel matrix level, and associated with a shift from morphological differentiation to continuous proliferation, with enhanced cell spreading resulting in eventual monolayer formation. Soluble complex carbohydrates, which inhibited capillary tubule formation on Matrigel without induction of cell spreading or monolayer formation, failed to impair Trx promotion of cell spreading and mono-layer formation, suggesting a shift away from carbohydrate-mediated cell/matrix adhesive interactions. Laminin peptides YIGRS and SIKVAV, which impaired tubule formation on Matrigel without inducing cell spreading or monolayer formation, partially impaired cell spreading upon Trx-treated Matrigel without restoring tubule formation, consistent with a potential role for laminin in Trx-mediated effects. Trx reduced laminin and destabilised laminin/galectin-3 complexes within Matrigel. Native purified EHS Laminin (also containing galectin-3), but not recombinant galectin-3, restored HMEC-1 capillary tubule formation on Trx-treated Matrigel. These data highlight a novel deregulatory effect of extracellular Trx upon morphological capillary differentiation that appears to depend upon the reduction of laminin and destabilisation of its interaction with galectin-3, possibly leading to galectin-3 neutralisation that shifts cell/matrix adhesive interactions away from being carbohydrate mediated and results in loss of proliferation-inhibiting and differentiation promoting cues from this tumor basement membrane matrix.
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PMID:Thioredoxin inhibits microvascular endothelial capillary tubule formation. 1464 68

Transient/chronic microenvironmental hypoxia that exists within a majority of solid tumors has been suggested to have a profound influence on tumor growth and therapeutic outcome. Since the functions of novel antioxidant proteins, peroxiredoxin I (Prx I) and II, have been implicated in regulating cell proliferation, differentiation, and apoptosis, it was of our special interest to probe a possible role of Prx I and II in the context of hypoxic tumor microenvironment. Since both Prx I and II use thioredoxin (Trx) as an electron donor and Trx is a substrate for thioredoxin reductase (TrxR), we investigated the regulation of Trx and TrxR as well as Prx expression following hypoxia. Here we show a dynamic change of glutathione homeostasis in lung cancer A549 cells and an up-regulation of Prx I and Trx following hypoxia. Western blot analysis of 10 human lung cancer and paired normal lung tissues also revealed an elevated expression of Prx I and Trx proteins in lung cancer tissues. Immunohistochemical analysis of the lung cancer tissues confirmed an augmented Prx I and Trx expression in cancer cells with respect to the parenchymal cells in adjacent normal lung tissue. Based on these results, we suggest that the redox changes in lung tumor microenvironment could have acted as a trigger for the up-regulation of Prx I and Trx in lung cancer cells. Although the clinical significance of our finding awaits more rigorous future study, preferential augmentation of the Prx I and Trx in lung cancer cells may well represent an attempt of cancer cells to manipulate a dynamic redox change in tumor microenvironment in a manner that is beneficial for their proliferation and malignant progression.
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PMID:Preferential elevation of Prx I and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues. 1470 16

Low selenium (Se) status increases angiogenesis by inducing the production of vascular endothelial growth factor (VEGF); however, the mechanism responsible for VEGF up-regulation has yet to be characterized. Se's ability to control cellular oxidative state through its incorporation into selenoproteins such as thioredoxin reductase (TrxR) may explain previous studies that connect Se status to tumor angiogenesis. Therefore, the focus of this study was to determine if altered VEGF expression and angiogenesis due to decreased Se levels are influenced by reduced TrxR activity. We found that chemical inhibition of TrxR in Se-sufficient endothelial cells (ECs) was associated with increases in VEGF and VEGF receptor expression, cell migration, proliferation, and angiogenesis to levels similar to those seen in Se-deficient ECs. Specific inhibition of glutathione peroxidase did not affect pro-angiogenic responses, indicating a unique role of the TrxR system during low Se status. These data correlate changes in TrxR activity with changes in VEGF expression and angiogenic development in ECs, which is significant because minimal mechanistic data exist that explain the role of Se in cancer prevention. Understanding the importance of the tumor microenvironment in contributing to angiogenic regulation has the potential to significantly impact breast cancer chemoprevention strategies by focusing on maintaining proper EC function within the mammary gland.
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PMID:Thioredoxin reductase regulates angiogenesis by increasing endothelial cell-derived vascular endothelial growth factor. 1562 70

Among the substances that attracted the attention of oncologists in recent years are selenium-containing compounds, both inorganic and organic. Several epidemiological studies have shown an inverse correlation between selenium intake and cancer incidence. In the experiments reported here, we compared the effects of 2 inorganic selenium-containing salts that differed in the level of selenium oxidation, selenite IV and selenate VI. We tested the effects of these 2 compounds on cell survival and growth, cell cycle processing, cell morphology, cytoskeleton, and lipid peroxidation in 3 human skin cell types: normal keratinocytes, melanocytes, and human melanoma cell line HTB140. The different effects of selenite and selenate on the viability, growth, and morphology of normal cells and tumor cells are reported and provide a base for future research and treatment of some neoplastic diseases. The attention is paid to cell apoptosis induced by selenite and not by selenate, and the effects of tested substances on thioredoxin reductase system are postulated.
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PMID:Differential effects of selenite and selenate on human melanocytes, keratinocytes, and melanoma cells. 1586 28

Selenium (Se), an essential trace element, is incorporated into selenoproteins as selenocysteine using insertion machinery, including UGA codon and selenocysteine insertion sequence (SECIS) element in the 3'-untranslated region (3'-UTR) of mRNA. To assess the biological effects of tumor cells exposed to the elevated, but nontoxic Se level on glutathione peroxidase (GPx1 [cellular] and GPx3 [extracellular]), thioredoxin reductase (TrxR), and selenoprotein P (SeP) mRNA expression, we introduced a semiquantitative reverse transcription-polymerase chain reaction technique for each selenoprotein transcript using beta-actin as a reference housekeeping gene in mouse fibroblasts (WEHI 164). Cell lines were cultured with 1.0, 2.5, and 5.0 ng of Se in 1 mL of medium for 3 and 7 d, apart from the control cell line with standard medium. It was found that Se exerts a statistically significant (p<0.05) effect only on GPx3 mRNA, referred to as the optical density (OD) ratio (GPx3/beta-actin). Moreover, the lowest Se level affected GPx3 mRNA expression more strongly than its highest concentrations. In an in vitro model applied in this study, GPx3 gene expression is most specific for Se supplementation.
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PMID:Effect of selenium on expression of selenoproteins in mouse fibrosarcoma cells. 1589 16


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