Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selenium (Se) has been reported to reduce the severity of MeHg-induced neurological deficits. Therefore, we investigated whether 24h. preincubation or 50min. coincubation with selenomethionine (SeMet) was effective in reducing methylmercury (MeHg)-induced cytotoxicity in C6-glioma and B35-neuronal cell lines. As indicators of cytotoxicity, reduced glutathione (GSH), reactive oxygen species (ROS) and mitochondrial activity (MTT) was assessed. Measurement of GSH with the fluorescent indicator MCB-monochlorobimane indicated that in SeMet preincubated C6 cells, MeHg treatment resulted in a significant (p<0.001) decrease in GSH levels as compared to coincubation group. Treatment with SeMet did not induce any significant changes in MTT activity in either of the cell lines as compared to the MeHg group. However, the amount of MeHg-induced ROS was significantly reduced (p<0.001) after SeMet preincubation in both the cell lines. The intracellular Se content was measured with high resolution-inductively coupled plasma mass spectrometry (HR-ICPMS). In both the cell lines the intracellular Se levels increased after pre- and coincubation with 20 and 50microM SeMet. However, the preincubation group exhibited increased Se content in both the cell lines and varied (p<0.001) from coincubation group. These differences in the Se content were maintained after 10microM MeHg treatment for 50min. In C6-gliomas, the cell associated-MeHg measurements using (14)C-labeled MeHg indicated a significant increase (p<0.001) in MeHg content in preincubated cells as compared to coincubated cells. These findings provide experimental evidence that preincubation with SeMet increases Se content in cells and prevents against increased MeHg-induced ROS generation.
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PMID:The in vitro effects of selenomethionine on methylmercury-induced neurotoxicity. 1916 24

Glutamine is an important source of energy for neoplastic tissues, and products of its metabolism include, among others, glutamate (Glu) and glutathione (GSH), the two molecules that play a key role in tumor proliferation, invasiveness and resistance to therapy. Glutamine hydrolysis in normal and transforming mammalian tissues alike, is carried out by different isoforms of glutaminases, of which the two major are liver-type glutaminase (LGA) and kidney-type glutaminase (KGA). This brief review summarizes available data on the expression profiles and activities of these isoenzymes in different neoplastic tissues as compared to the tissues of origin, and dwells on recent work demonstrating effects of manipulation of glutaminase expression on tumor growth. A comment is devoted to the emerging evidence that LGA, apart from degrading Gln for metabolic purposes, is involved in gene transcription; its enforced overexpression in glioma cells was found to reduce their proliferation and migration.
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PMID:Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. 1942 9

Nuclear factor-kappaB (NF-kappaB) is a pleiotropic transcription factor that generally enhances cellular resistance to apoptotic cell death. It has been shown to be constitutively active in some cancers and is being pursued as potential anticancer target. Sulfasalazine which is used clinically to treat Crohn's disease has emerged as a potential inhibitor of NF-kappaB and has shown promising results in two pre-clinical studies to target primary brain tumors, gliomas. Once digested, sulfasalazine is cleaved into sulfapyridine and 5-aminosalicylic acid (5-ASA; mesalamine) by colonic bacteria, and the latter, too, is reported to suppress NF-kappaB activity. We now show that glioma cells obtained from patient biopsies or glioma cell lines do not show significant constitutive NF-kappaB activation, unless exposed to inflammatory cytokines. This does not change when gliomas are implanted into the cerebrum of severe combined immun-deficient mice. Nevertheless, sulfasalazine but not its cleaved form 5-ASA caused a dose-dependent inhibition of glioma growth. This effect was entirely attributable to the inhibition of cystine uptake via the system x(c)(-) cystine-glutamate transporter. It could be mimicked by S-4-carboxy-phenylglycine (S-4-CPG) a more specific system x(c)(-) inhibitor, and lentiviral expression of a constitutively active form of IkappaB kinase b was unable to overcome the growth retarding effects of sulfasalazine or S-4-CPG. Both drugs inhibited cystine uptake causing a chronic depletion of intracellular GSH and consequently compromised cellular redox defense which stymied tumor growth. This data suggests that system x(c)(-) is a promising therapeutic target in gliomas and possibly other cancers and that it can be pharmacologically inhibited by Sulfasalazine, an FDA-approved drug.
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PMID:Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-kappaB. 1945 25

Methylmercury (MeHg) is a neurotoxicant which enters the brain and may cause permanent change. Thus, the properties of MeHg transport across cell membranes are a key factor in designing an appropriate model for MeHg neurotoxicity. This study uses cell cultures to examine the uptake and efflux mechanisms of methylmercury in C6 glioma, B35 neuroblastoma and rat brain endothelial (RBE4) cells. The cellular uptake and efflux of MeHg was investigated using (14)C-labeled MeHg. The uptake of MeHg-chloride was temperature-independent while the uptake of MeHg-L-cysteine was temperature-dependent in all the three cell types. This indicates that uptake of MeHg-chloride is due to passive diffusion and uptake of MeHg-L-cysteine is due to a protein carrier. Substrates of the amino acid transport system L inhibited uptake of MeHg-L-cysteine in C6 and RBE4 cells, but not B35 cells, indicating a role for system L in MeHg-uptake in the former two. Probenecid, Na(+)-free medium, MeHg and several L-amino acids did not alter the efflux of MeHg from C6 and RBE4 cells. The amino acids L-cysteine and cystine however, increased the efflux. Both cysteine and cystine are important in the generation of glutathione (GSH), suggesting the involvement of GSH in MeHg efflux. HgCl(2) at low concentrations (0.5 and 1.0 microM) decreased the MeHg efflux and at high concentrations (5.0 and 10.0 microM) increased the efflux. This inhibiting effect of HgCl(2) at low concentrations is possibly due to binding to GSH while the effect of high HgCl(2) concentrations is attributed to disrupted membrane integrity, as measured by Trypan blue. This study demonstrates differing transport mechanisms of MeHg in the cell lines C6, B35 and RBE4.
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PMID:Uptake and efflux of methylmercury in vitro: comparison of transport mechanisms in C6, B35 and RBE4 cells. 1954 Sep 10

The x(c)(-) cystine/glutamate antiporter has been implicated in GSH-based chemoresistance because it mediates cellular uptake of cystine/cysteine for sustenance of intracellular GSH levels. Celastrol, isolated from a Chinese medicinal herb, is a novel heat shock protein 90 (Hsp90) inhibitor with potent anticancer activity against glioma in vitro and in vivo. In search of correlations between growth-inhibitory potency of celastrol in NCI-60 cell lines and microarray expression profiles of most known transporters, we found that expression of SLC7A11, the gene encoding the light chain subunit of x(c)(-), showed a strong negative correlation with celastrol activity. This novel gene-drug correlation was validated. In celastrol-resistant glioma cells that highly expressed SLC7A11, sensitivity to celastrol was consistently increased via treatment with x(c)(-) inhibitors, including glutamate, (S)-4-carboxyphenylglycine, sulfasalazine, and SLC7A11 small interfering RNA. The GSH synthesis inhibitor, buthionine sulfoximine, also increased celastrol sensitivity, whereas the GSH booster, N-acetylcysteine, suppressed its cytotoxicity. Furthermore, the glioma cell lines were dependent on x(c)(-)-mediated cystine uptake for viability, because cystine omission from the culture medium resulted in cell death and treatment with sulfasalazine depleted GSH levels and inhibited their growth. Combined treatment of glioma cells with sulfasalazine and celastrol led to chemosensitization, as suggested by increased celastrol-induced cell cycle arrest, apoptosis, and down-regulation of the Hsp90 client protein, epidermal growth factor receptor. These results indicate that the x(c)(-) transporter provides a useful target for glioma therapy. x(c)(-) inhibitors such as sulfasalazine, a Food and Drug Administration-approved drug, may be effective both as an anticancer drug and as an agent for sensitizing gliomas to celastrol.
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PMID:Pharmacogenomic approach reveals a role for the x(c)- cystine/glutamate antiporter in growth and celastrol resistance of glioma cell lines. 2000 6

Changes in cellular energy and redox states in the C6 glioma cells exposed to increasing concentrations of either Zn or Se were studied to examine whether different elements cause different patterns of changes in cellular metabolism. Following a 3-h exposure, both Zn and Se(+4) caused dose-dependent decreases in cell viability and total adenosine nucleotides (TAN = ATP + ADP + AMP). In addition, Zn caused a dose-dependent increase in cellular ATP/TAN and a decrease in the ADP/TAN and AMP/TAN. These changes resulted in a significant increase in energy charge potential (ECP = [ATP + 0.5ADP]/TAN). Se(+4), on the other hand, caused a dose-dependent decrease in ATP/TAN but an increase in both ADP/TAN and AMP/TAN, resulting in a dose-dependent decrease in ECP. Both Zn and Se(+4) caused a dose-dependent decrease in GSH/GSSG and an increase in GSH + GSSG when compared to TAN. In contrast to Zn and Se(+4), the nontoxic Se(+6) caused no significant changes in cellular energy states but reduced the GSH/GSSG ratio from 3.14 +/- 0.49 to 2.05 +/- 0.29, which could be explained by the effect of Se on enzymes responsible for GSH metabolism. As the cellular ATP level has been considered an important element that mediates the mode of cell death, it was suggested that a significant increase in ATP/TAN upon exposure to Zn would indicate that cell death occurred via apoptosis, while Se(+4) caused a different pattern of cell death. This was confirmed by the appearance of cells with fragmented nucleus in cells treated with Zn, but not Se(+4) and Se(+6). The results demonstrated that different chemicals caused different patterns of metabolic changes. The correlation between metabolic changes and the mode of cell death was discussed.
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PMID:Energy and redox States in the c6 glioma cells following acute exposure to zn, se(+4), and se(+6) and the correlation with apoptosis. 2002 Oct 36

Our earlier studies have shown that simultaneous inhibition of glycolysis and pentose phosphate pathway using 2-deoxy-d-glucose (2-DG, an inhibitor of glycolysis) and 6-aminonicotinamide (6-AN, an inhibitor of pentose phosphate pathway) lead to metabolic oxidative stress (MOS), resulting in radiosensitization in malignant cells. Present study was carried out to investigate the effects of 2-DG and 6-AN on intricately regulated endogenous antioxidant defense against MOS during radiosensitization by this combination. Two human tumor cell lines {Head and Neck Squamous carcinoma (KB) and Glioma (BMG-1)} and one non-malignantly transformed cell line (human embryonic kidney, HEK) were used in this study. The presence of 2-DG and 6-AN (added just before irradiation) for 4h, significantly decreased the clonogenicity and metabolic viability of KB and BMG-1 cell lines, while no significant change was seen in HEK cells. Accumulation of ROS was observed only in malignant cell lines, which displayed a compromised redox status evident from enhanced NADP(+)/NADPH and GSSG/GSH ratios and a concomitant decrease in glutathione reductase level and activity at 24h following treatment. The levels and activities of Cu, Zn-SOD and Mn-SOD increased with MOS and were accompanied by a decreased GPx and unaltered catalase activity and level. These results suggest that non-coordinated expression of antioxidant defense, besides compromised redox status, led to selective radiosensitization in the malignant cells.
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PMID:Metabolic oxidative stress induced by a combination of 2-DG and 6-AN enhances radiation damage selectively in malignant cells via non-coordinated expression of antioxidant enzymes. 2036 70

We endeavored here to shed light on the supply of glutathione (GSH) precursors from glial cells to neurons and on the interference of ammonia with this process. Administration of ammonium chloride (ammonia) via a microdialysis probe to the rat prefrontal cortex rapidly increased GSH content in the microdialysates. The increase was abrogated by the inhibitor of astrocytic energy metabolism fluoroacetate and the inhibitor of glutathione synthesis buthionine sulfoximine. GSH in the microdialysates was significantly elevated in rats with simple hyperammonemia (HA) or hepatic encephalopathy (HE) (three ip administrations of ammonium acetate or thioacetamide, respectively, at 24-h intervals), only when microdialysis was carried out in the presence of a gamma-glutamyltranspeptidase (gammaGT) inhibitor acivicin. Extracellular GSH increased in cultured rat cortical astrocytes treated with 5mM ammonia for 1 h, but not for 3-72 h, which was the period of increased gammaGT activity. GSH remained increased during the whole 72-h incubation with 5 or 10mM ammonia in C6 glioma cells, where gammaGT activity is intrinsically low and was not increased by ammonia. Collectively, the results suggest that in rats with HA or HE ammonia specifically promote GSH synthesis and export from astrocytes and increase its extracellular degradation, which may improve the availability of precursors for GSH synthesis in neurons and their resistance to ammonia toxicity.
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PMID:Direct exposure to ammonia and hyperammonemia increase the extracellular accumulation and degradation of astroglia-derived glutathione in the rat prefrontal cortex. 2053 Feb 33

Methylmercury (MeHg), an environmental toxicant primarily found in fish and seafood poses a dilemma to both consumers and regulatory authorities given the nutritional benefits of fish consumption vs. possible adverse neurological damage caused by MeHg. The present study addresses whether supplementation with 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), alters the neuro-oxidative effects of MeHg in C6-glioma and B35-neuronal cell lines. As indicators of cytotoxicity, reduced glutathione (GSH), reactive oxygen species (ROS) and mitochondrial activity (MTT) were measured. The cellular mercury (Hg) content was measured with high resolution-inductively coupled plasma mass spectrometry (HR-ICPMS). The amount of MeHg-induced ROS was significantly reduced (p<0.05) after treatment with 50muM Trolox in C6 glial cell line. However, treatment with Trolox did not induce any significant increase in GSH levels or MTT activity in either of the cell lines. In addition, treatment with Trolox did not induce any significant changes in intracellular MeHg levels. The MeHg and Trolox treated C6 glial cell line differed significantly (p<0.05) from the B35 cell line for MTT, ROS and GSH activity. These findings provide experimental evidence that preincubation with Trolox prevents MeHg-induced ROS generation in C6 glial cell line by quenching of free radicals and not by changes in intracellular GSH or MeHg content.
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PMID:The in vitro effects of Trolox on methylmercury-induced neurotoxicity. 2063 24

The neurotoxic effects of mercury (II) chloride, methylmercury (MeHg) and cadmium chloride on astrocytes were modelled using C6 glioma cell cultures. All three compounds were cytotoxic to these cells with an order of potency of cadmium > MeHg > mercurychloride. Addition of reduced glutathione (GSH) to the media protected the cells in all three cases, whereas depletion of GSH with l-buthionine-S,R-sulfoximine enhanced the toxicity of cadmium and mercury chloride but not MeHg. The effects of subcytotoxic concentrations of these compounds on intracellular GSH levels were assessed using chlorobimane staining. All three showed a similar type of effect-an initial depletion of GSH followed by an increase to levels greater than in untreated cells. For mercury chloride-exposed cells (0.37-3.7 muM), the initial depletion occurred over 4 hr with the cells recovering by 7 hr and increases in the GSH content seen after 24 hr. With cadmium or MeHg (0.04-4 muM), the initial depletion was more protracted, with treated cells having less GSH than control cells for 4-7 hr. Glutathione S-transferase activity in the cells was increased after 24 hr of exposure to all three metals to about 200% of control values. These results show that some components of the glutathione system in C6 glioma cells are activated after exposure to heavy metal compounds.
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PMID:Protective roles of glutathione in the toxicity of mercury and cadmium compounds to C6 glioma cells. 2065 Feb 4


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