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)

Elevated levels of extracellular glutamate ([Glu]o) cause uncontrolled Ca2+ increases in most neurons and are believed to mediate excitotoxic brain injury following stroke and other nervous system insults. In the normal brain, [Glu]o is tightly controlled by uptake into astrocytes. Because the vast majority of primary brain tumors (gliomas) are derived from astrocytes, we investigated glutamate uptake in glioma cells surgically isolated from glioma patients (glioblastoma multiforme) and in seven established human glioma cell lines, including STTG-1, D-54 MG, D-65 MG, U-373 MG, U-138 MG, U-251 MG, and CH-235 MG. All glioma cells studied showed impaired glutamate uptake, with a Vmax < 10% that of normal astrocytes. Moreover, rather than removing glutamate from the extracellular fluid, glioma cells release large amounts of glutamate, resulting in elevations of [Glu]o in excess of 100 microM within hours in a space that is 1000-fold larger than the cellular volume. Exposure of cultured hippocampal neurons to glioma-conditioned medium elicited sustained [Ca2+]i elevations that were followed by widespread neuronal death. Similarly, coculturing of hippocampal neurons and glioma cells, either with or without direct contact, resulted in neuronal death. Glioma-induced neuronal death could be completely prevented by treating neurons with the N-methyl-D-aspartate receptor antagonists MK-801/D(-)-2-amino-5-phosphonopentanoic acid or by depletion of glutamate from the medium. Interestingly, several phenylglycine derivatives including the metabotropic glutamate receptor agonist/antagonist (S)-4-carboxyphenylglycine (S-4CPG) potently and selectively inhibited glutamate release from glioma cells and prevented neurotoxicity. These data suggest that growing glioma tumors may actively kill surrounding neuronal cells through the release of glutamate. This glutamate release may also be responsible in part for tumor-associated seizures that occur frequently in conjunction with glioma. These data also suggest that neurotoxic release of glutamate by gliomas may be prevented by phenylglycine derivatives, which may thus be useful as an adjuvant treatment for brain tumors.
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PMID:Glioma cells release excitotoxic concentrations of glutamate. 1048 87

Elevated levels of extracellular glutamate ([Glu](o)) can induce seizures and cause excitotoxic neuronal cell death. This is normally prevented by astrocytic glutamate uptake. Neoplastic transformation of human astrocytes causes malignant gliomas, which are often associated with seizures and neuronal necrosis. Here, we show that Na(+)-dependent glutamate uptake in glioma cell lines derived from human tumors (STTG-1, D-54MG, D-65MG, U-373MG, U-251MG, U-138MG, and CH-235MG) is up to 100-fold lower than in astrocytes. Immunohistochemistry and subcellular fractionation show very low expression levels of the astrocytic glutamate transporter GLT-1 but normal expression levels of another glial glutamate transporter, GLAST. However, in glioma cells, essentially all GLAST protein was found in cell nuclei rather than the plasma membrane. Similarly, brain tissues from glioblastoma patients also display reduction of GLT-1 and mislocalization of GLAST. In glioma cell lines, over 50% of glutamate transport was Na(+)-independent and mediated by a cystine-glutamate exchanger (system x(c)(-)). Extracellular L-cystine dose-dependently induced glutamate release from glioma cells. Glutamate release was enhanced by extracellular glutamine and inhibited by (S)-4-carboxyphenylglycine, which blocked cystine-glutamate exchange. These data suggest that the unusual release of glutamate from glioma cells is caused by reduction-mislocalization of Na(+)-dependent glutamate transporters in conjunction with upregulation of cystine-glutamate exchange. The resulting glutamate release from glioma cells may contribute to tumor-associated necrosis and possibly to seizures in peritumoral brain tissue.
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PMID:Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. 1059 60

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

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