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)

Cyclooxygenase-2 (COX-2; EC 1.14.99.1) RNA message abundance in 25 control and Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-confirmed sporadic Alzheimer's disease (AD) brains is remarkably heterogeneous when compared with 55 other AD brain RNA message levels that were previously characterized (Lukiw and Bazan: J Neurosci Res 50:937-945, 1997). Examination of nuclear protein extracts (NPXTs) that were derived from control and AD-affected brain neocortical nuclei (n = 20; age range, 60-82 years; postmortem interval, 0.5-6.5 hours) by using gel shift, gel supershift, and cold oligonucleotide competition assay revealed a highly significant relationship between the extent of inflammatory transcription factor, nuclear factor (NF)-kappaB: DNA binding and the abundance of the COX-2 RNA signal (P < 0.0001; analysis of variance). No strong correlation with AP-1-DNA binding was noted (P > 0.045). These data are the first linking inflammation-related transcription factor NF-KB-DNA binding to up-regulation of transcription from a key inflammatory gene, COX-2, in both normally aging brain and in AD-affected neocortex. Systematic deletion of NF-KB-DNA binding sites in human COX-2 promoter constructs attenuates COX-2 transcriptional induction by mediators of inflammation. Strong NF-kappaB-DNA binding has been reported previously to temporally precede COX-2 gene transcription in human epithelial (A549), hamster B-cell (HIT-T15), human endothelial (HUVEC), human lymphoblast (IM9), human fibroblast (IMR90), rat glioma/mouse neuroblastoma (NG108-15), human keratinocyte (NHEK), mouse fibroblast (NIH 3T3), rat neuroblastoma (SH-SY5Y) cell lines and in mouse and rat brain hippocampus, indicating a highly conserved inflammatory signaling pathway that is common to diverse species and cell types. The mouse, rat, and human COX-2 immediate promoters, despite 7.5 x 10(7) years of DNA sequence divergence, each retain multiple recognition sites specific for NF-kappaB-DNA binding. These data suggest that basic gene induction mechanisms, which have been conserved over long periods of evolution, that increase NF-kappaB-DNA binds ing may be fundamental in driving transcription from inflammation-related genes, such as COX-2, that operate in stressed tissues, in normally aging cell lines, and in neurodegenerative disorders that include AD brain.
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PMID:Strong nuclear factor-kappaB-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic Alzheimer's disease superior temporal lobe neocortex. 972 29

The antitumor effects of the selective cyclooxygenase (COX)-2 inhibitor SC-236 alone and in combination with radiation were investigated using the human glioma cell line U251 grown in monolayer culture and as tumor xenografts. On the basis of Western and Northern blot analyses, these cells express COX-2 protein and mRNA to levels similar to those in the human colon carcinoma cell line HT29. Treatment of U251 cells in monolayer culture with 50 microM SC-236 resulted in a time-dependent decrease in cell survival as determined by a clonogenic assay. The cell death induced by SC-236 was associated with apoptosis and the detachment of cells from the monolayer. After 2 days of drug treatment, the cells that remained attached were exposed to graded doses of radiation, and the clonogenic assay was performed. Comparison of the survival curves for drug-treated and untreated cultures revealed that SC-236 enhanced radiation-induced cell death. In these combination studies, SC-236 treatment resulted in a dose-enhancement factor of 1.4 at a surviving fraction of 0.1, with the surviving fraction at 2 Gy (SF2) reduced from 0.61 to 0.31. These data indicate that in vitro SC-236 induces U251 apoptotic cell death and enhances the radiosensitivity of the surviving cells. To extend these investigations to an in vivo situation, U251 glioma cells were grown as tumor xenografts in the hind leg of nude mice, and SC-236 was administered in drinking water. SC-236 alone slowed tumor growth rate, and when administered in combination with local irradiation, SC-236 caused a greater than additive increase in tumor growth delay. These in vitro and in vivo results suggest that the selective inhibition of COX-2 combined with radiation has potential as a cancer treatment.
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PMID:Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. 1087 7

Cyclooxygenase (COX) synthesizes bioactive prostaglandins from arachidonic acid, and there are COX-1 and COX-2 isoforms with distinct pathophysiological functions. Recent studies demonstrated that COX-2 expression was up-regulated in the brain of patients with Alzheimer's disease. We established mouse neuroblastoma x rat glioma hybrid NG108-15 cells stably expressing human COX-2. The COX-2-expressing cells showed 3- to 4-fold increases in both COX activity and prostaglandin E(2) production. The mRNA level of amyloid precursor protein (APP) was elevated by approximately 2-fold in the COX-2-expressing cells compared with mock-transfected cells. Amyloid beta-peptide and a secreted form of APP, both derived from APP by proteolysis was also increased. Interestingly, neurite outgrowth was stimulated in the COX-2-expressing cells with concomitant reduction of the cell proliferation rate. A selective COX-2 inhibitor (JTE-522) and a nonselective COX inhibitor (indomethacin) suppressed production of amyloid beta-peptide and a secreted form of APP by inhibition of APP mRNA level, suggesting that COX-2 plays important roles in the neurodegenerative processes of Alzheimer's disease.
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PMID:Cyclooxygenase-2 stimulates production of amyloid beta-peptide in neuroblastoma x glioma hybrid NG108-15 cells. 1118 Oct 73

Several studies have demonstrated that inhibitors of cyclooxygenase (COX) attenuate various neuronal injuries and age-dependent demented conditions. From these findings, we proposed to test the effect of age on COX activity and its possible suppression by the antiaging action of dietary restriction in the rat brain. The status of reactive oxygen species (ROS) was also assessed to correlate with COX activity to delineate the underlying mechanism of the altered COX activity during aging. These results showed that COX activity significantly increased in 24-month-old rats compared with 6-month-old rats in an ad libitum group. Interestingly, mRNA and protein levels of COX-2 showed little corresponding age-related change. The formation of ROS was found to increase gradually with age in ad libitum fed rats. However, dietary restriction suppressed the increase at the age of 24 months. To substantiate the relationship between ROS and COX activity when the rats were 24 months of age, we conducted in vitro experiments with a C6 glioma cell line. Together, it is concluded that increased COX activity with age is due to the activation of COX catalytic reaction by ROS without increased gene expression of COX-2 and that it is related to the increased pro-oxidant status in aged rats.
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PMID:Age-related increase of brain cyclooxygenase activity and dietary modulation of oxidative status. 1158 27

The fruit hull of mangosteen, Garcinia mangostana L., has been used for many years as a medicine for treatment of skin infection, wounds, and diarrhea in Southeast Asia. In the present study, we examined the effect of gamma-mangostin, a tetraoxygenated diprenylated xanthone contained in mangosteen, on arachidonic acid (AA) cascade in C6 rat glioma cells. gamma-Mangostin had a potent inhibitory activity of prostaglandin E2 (PGE2) release induced by A23187, a Ca2+ ionophore. The inhibition was concentration-dependent, with the IC50 value of about 5 microM. gamma-Mangostin had no inhibitory effect on A23187-induced phosphorylation of p42/p44 extracellular signal regulated kinase/mitogen-activated protein kinase or on the liberation of [14C]-AA from the cells labeled with [14C]-AA. However, gamma-mangostin concentration-dependently inhibited the conversion of AA to PGE2 in microsomal preparations, showing its possible inhibition of cyclooxygenase (COX). In enzyme assay in vitro, gamma-mangostin inhibited the activities of both constitutive COX (COX-1) and inducible COX (COX-2) in a concentration-dependent manner, with the IC50 values of about 0.8 and 2 microM, respectively. Lineweaver-Burk plot analysis indicated that gamma-mangostin competitively inhibited the activities of both COX-1 and -2. This study is a first demonstration that gamma-mangostin, a xanthone derivative, directly inhibits COX activity.
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PMID:Inhibition of cyclooxygenase and prostaglandin E2 synthesis by gamma-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells. 1175 76

We have previously identified thromboxane synthase as an important regulator of glioma cell migration. Inhibitors of this enzyme abrogate cell motility and induce apoptosis. However, the formation rate of thromboxanes is indirectly dependent on the activity of cyclo-oxygenase, which represents the rate-limiting step in the synthesis of prostaglandins and thromboxanes. In this study we have analyzed the expression of COX-1 and COX-2 in glioma cell lines and biopsies of glial tumors. In normal glia no expression of both COX isoforms was present, however, reactive astrocytes and glial tumors of all grades demonstrated expression of both COX-1 and COX-2. In contrast to inhibitors of thromboxane synthase, selective and non-selective cyclo-oxygenase inhibitors did not block cell motility. Specific COX-2 inhibitors resulted in growth inhibition and induction of intracellular DNA fragmentation indicative of apoptotic cell death. Treatment of glioma cells with thromboxane synthase inhibitors had a synergistic effect on induction of apoptosis by camptothecin, whereas COX inhibitors had not. Furthermore, combined treatment using COX-2 inhibitors and specific thromboxane synthase inhibitors did not show a synergistic increase of apoptosis. These data indicate that COX inhibitors and thromboxane synthase inhibitors influence apoptosis in glioma cells through different pathways. We hypothesize that, in contrast to the COX-2 inhibitors, thromboxane synthase inhibitors block the invasive phenotype of glioma cells and therefore increase the pro-apoptotic disposition of the cells and increase the susceptibility to induced apoptosis. This effect may be independent of prostaglandin synthesis controlled by cyclo-oxygenases.
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PMID:Cyclo-oxygenase inhibitors and thromboxane synthase inhibitors differentially regulate migration arrest, growth inhibition and apoptosis in human glioma cells. 1180 49

Eicosanoids constitute a large family of biologically active lipid mediators that are produced by two enzyme classes, cyclooxygenases (COX-1 and COX-2) and lipoxygenases (5-LO, 12-LO, and 15-LO). Increasing evidence suggests that in addition to a variety of epithelial malignancies, the two most common types of human brain tumour, gliomas and meningiomas, aberrantly overexpress eicosanoid producing enzymes and release a spectrum of eicosanoids that may promote tumorigenesis and the development of peritumorous brain oedema. Glioma and meningioma cells are killed in vitro and in animal models when exposed to COX-2 and 5-LO inhibitors, and their effectiveness is under investigation in clinical trials for treatment of patients with malignant brain tumours. However, despite research into the role of the eicosanoid cascade in the tumorigenesis of human brain tumours, many important questions remain unanswered. Current and newer agents that specifically target key players of the eicosanoid cascade could change the approach to treating brain tumours, because their benefits may lie in their synergism with conventional cytotoxic treatments and/or with other novel agents targeted against other procarcinogenic pathways.
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PMID:The eicosanoid cascade: possible role in gliomas and meningiomas. 1469 27

Prostaglandin H synthase (PHS) is a key enzyme in the synthesis of prostaglandins (PGs). Recently, enhanced expression of PHS-2 in brain tumors and the correlation between the PHS-2 level and the histopathological grade of glioma has been reported. Furthermore, in vitro inhibition of glioma cell growth by a specific PHS-2 inhibitor, NS398, has been demonstrated. It has also been shown that prostaglandin E2 (PGE2) contributes to colon carcinogenesis by binding to the prostaglandin E receptor subtype EP1. We therefore evaluated the effects of NS398 and two EP1 antagonists, SC51089 and AH6809, on glioma cell lines. To evaluate mechanisms of NS398's action, two glioma cell lines, a PHS-2-positive cell line (KMG4) and a PHS-2-deficient cell line (A 172), were used. NS398 inhibited both the anchorage-dependent and -independent growth of glioma cell lines regardless of PHS-2 expression, suggesting that some PHS-2-independent mechanisms underlie the antineoplastic effect of NS398. However, the antineoplastic effect was attenuated by the addition of PGE2, which is one of the main products of PHS, suggesting the predominant mechanism is PHS-dependent. The EP1 antagonists, SC51089 and AH6809, inhibited the growth of glioma cell lines in vitro. Furthermore, NS398 or SC51089 slowed tumor growth in vivo, which was assessed using KMG4 tumor xenografts on SCID mice. PHS-2 inhibitors and EP1 antagonists might be useful in the prevention and/or treatment of glioma.
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PMID:Inhibition of human glioma cell growth by a PHS-2 inhibitor, NS398, and a prostaglandin E receptor subtype EP1-selective antagonist, SC51089. 1501 58

Previous studies have demonstrated that inhibitors of the arachidonic acid metabolism block migration and sensitise human glioma cells to treatment inducing apoptosis. This paradigm may provide a new concept for anti-invasive treatment strategies targeting invasive glioma cells. However, the effect of such treatment on other cellular elements in glial tumours such as endothelial cells is unknown. In this study we have analysed the expression of metabolites of the arachidonic acid pathway in endothelial cells in vitro and in vivo and we have assessed the influence of inhibitors of this pathway on motility, capillary like tube formation, and apoptosis in human endothelial cells. Human endothelial cells (HUVEC) in culture showed expression for thromboxane synthase and both isoforms of cyclo-oxygenase, COX-1 and COX-2. Immunostaining demonstrated low levels of COX-1 expression in capillaries and larger vessels of normal brain and moderately elevated levels of this enzyme in small vessels of brain tumours of various grades. Both thromboxane synthase and COX-2 expression was limited to endothelial cells found in anaplastic gliomas and glioblastomas. Thromboxane synthase inhibitors strongly decreased endothelial cell migration in HUVEC in vitro and capillary like tube formation was strongly inhibited by the compound at a similar dose range. The non-selective cyclo-oxygenase inhibitor ASA and the selective COX-2 inhibitor sulindac only had a minor effect on endothelial cell migration, however, the COX-2 inhibitor sulindac showed a synergistic effect with the thromboxane synthase inhibitor. Thromboxane synthase inhibitors induced apoptosis in endothelial cells as demonstrated by intracellular histone-complexed DNA fragmentation. These data suggest that inhibitors of thromboxane synthase influence migration and apoptosis in both human glioma cells and human endothelial cells. An anti-invasive treatment strategy using this class of compounds may therefore not only sensitise glioma cells to conventional treatments inducing apoptosis but may also be supported by an anti-angiogenic effect.
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PMID:Inhibition of the arachidonic acid metabolism blocks endothelial cell migration and induces apoptosis. 1511 86

Cannabinoids have been implicated in the reduction of glioma growth. The present study investigated a possible relationship between the recently shown induction of cyclooxygenase (COX)-2 expression by the endocannabinoid analog R(+)methanandamide [R(+)-MA] and its effect on the viability of H4 human neuroglioma cells. Incubation with R(+)-MA for up to 72 h decreased the cellular viability and enhanced accumulation of cytoplasmic DNA fragments in a time-dependent manner. Suppression of R(+)-MA-induced prostaglandin (PG) E2 synthesis with the selective COX-2 inhibitor celecoxib (0.01-1 microM) or inhibition of COX-2 expression by COX-2-silencing small-interfering RNA was accompanied by inhibition of R(+)-MA-mediated DNA fragmentation and cell death. In contrast, the selective COX-1 inhibitor SC-560 was inactive in this respect. Cells were also protected from apoptotic cell death by other COX-2 inhibitors (NS-398 [[N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide]] and diclofenac) and by the ceramide synthase inhibitor fumonisin B1, which interferes with COX-2 expression by R(+)-MA. Moreover, the proapoptotic action of R(+)-MA was mimicked by the major COX-2 product PGE2. Apoptosis and cell death by R(+)-MA were not affected by antagonists of cannabinoid receptors (CB1, CB2) and vanilloid receptor 1. In further experiments, celecoxib was demonstrated to suppress apoptotic cell death elicited by anandamide, which is structurally similar to R(+)-MA. As a whole, this study defines COX-2 as a hitherto unknown target by which a cannabinoid induces apoptotic death of glioma cells. Furthermore, our data show that pharmacological concentrations of celecoxib may interfere with the proapoptotic action of R(+)-MA and anandamide, suggesting that cotreatment with COX-2 inhibitors could diminish glioma regression induced by these compounds.
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PMID:Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells. 1536 50


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