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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gliomas in vitro exhibit density-limited growth upon the attainment of confluency, an effect usually attributed to cell-cell contact inhibition. Since gliomas have been demonstrated to secrete an array of soluble factors which can enhance tumor growth, we undertook this study to ascertain whether production of soluble factors by the tumor may also inhibit growth in an autocrine manner, and whether production of such factors is associated with the growth phase of the glioma. We observed that cell-conditioned medium (supernatants) from non-confluent glioma cultures induced growth, while confluent culture supernatants produced pronounced growth suppression. These latter supernatants enhanced proliferation of non-transformed astrocytes. Supernatants derived from all stages of confluency produced inhibition of lymphocyte proliferation. To characterize these factors, dialyzed supernatant was tested and found to continue to produce lymphocyte suppression but no glioma growth limitation. Growth of tumors in indomethacin or in acetylsalicylic acid to abolish prostanoid synthesis abrogated the inhibitory influence on glioma growth but only partially reversed the lymphocyte suppressive capacity. These studies suggest that gliomas do produce a growth phase dependent autocrine inhibitory factor(s), and that the production of these small molecular weight factors is at least partially under control of the cyclooxygenase pathway.
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PMID:Production of soluble autocrine inhibitory factors by human glioma cell lines. 150 57

Endothelin-1, endothelin-3, and the snake venom toxin sarafotoxin S6b stimulate the hydrolysis of phosphatidylinositol by phospholipase C with similar potencies in primary cultures of astrocytes prepared from rat brain cortex. In indo 1-loaded cells, endothelin-1, endothelin-2, endothelin-3, and sarafotoxin induce the rapid mobilization of intracellular Ca2+ stores and promote a more slowly developing influx of Ca2+. These responses were insensitive to pertussis toxin and to inhibitors of cyclooxygenase and lipoxygenase. Similar actions of endothelins and sarafotoxin were observed using astrocytes from the cerebellum and glioma cells from the C6 and NN cell lines. The endothelin receptor of astrocytes differs from the receptor previously characterized in endothelial cells from brain microvessels in that it has a high affinity for endothelin-3. Thus, brain endothelin-1 and endothelin-3 have different target cells in the brain and may have different functions.
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PMID:Astrocytes are target cells for endothelins and sarafotoxin. 218 55

Human glioblastoma cells incubated in the presence of inhibitors of eicosanoid biosynthesis show decreased cellular proliferation without cytotoxicity. We studied the ultrastructural morphology of a human glioblastoma cell line cultured with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, or 5,8,11,14-eicosatetraynoic acid, a cyclooxygenase and lipoxygenase inhibitor. When glioblastoma cells were treated for 3 days with antiproliferative concentrations of either agent, they shared many morphological characteristics, including evidence for increased astrocytic differentiation with only limited signs of toxicity. The inhibited glioma cells demonstrated an increase in the number and length of astrocytic processes containing greater numbers of glial filaments, and the NDGA-treated cells also demonstrated extensive lateral pseudopod formation along the processes. The glioblastoma cell shape also became more elongated, losing the usual nuclear lobularity and nuclear inclusions, especially in NDGA-treated cells. Many cytoplasmic organelles packed the cytosol of the inhibited glioma cells, including prominent Golgi apparatus, dilated smooth endoplasmic reticulum evolving into dilated vesicles, cytoplasmic vacuoles, and numerous concentric laminations. There was limited evidence for toxicity, however, as the mitochondria were more pleomorphic with some mitochondrial distention and disruption of the cristae along with an increase in cytoplasmic vacuolization. We conclude that the inhibitors of eicosanoid biosynthesis, NDGA and 5,8,11,14-eicosatetraynoic acid, not only suppress glioblastoma cell proliferation, but also induce increased astrocytic differentiation.
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PMID:Ultrastructural evidence for differentiation in a human glioblastoma cell line treated with inhibitors of eicosanoid metabolism. 223 52

Glioma C62B cells were incubated for 18 h with [1-14C]arachidonic acid. Most (80%) of the added [1-14C] arachidonic acid was taken into the intracellular pool; less than 1% of the intracellular [1-14C]arachidonic acid remained unesterified; the rest was present in glycerophospholipids. Acetylcholine stimulation of the prelabeled cells resulted in the rapid accumulation of free [1-14C]arachidonic acid, presumably liberated by hydrolysis from phospholipids. Labeled unesterified [1-14C]arachidonic acid peaked by 90 s and returned to basal levels by 5 min. Paralleling the transient increase of unesterified [1-14C]arachidonic acid were increases in level of radioactivity in an unidentified lipoxygenase metabolite of arachidonic acid and of radioactive phosphatidic acid. The release of arachidonic acid induced by acetylcholine or carbachol was blocked by muscarinic but not nicotinic receptor antagonists; adrenergic or histaminergic receptor agonists were ineffective at stimulating arachidonic acid liberation. In contrast to the transient effects of stimulation with cholinergic agonists, stimulation with the divalent cation ionophore A23187 resulted in a linear increase in the accumulation of liberated arachidonic acid for at least 1 h. Furthermore, the pattern of metabolites synthesized from arachidonic acid in response to ionophore stimulation was more complex than that observed following cholinergic stimulation and included also several metabolites derived from cyclooxygenase activity. We conclude that muscarinic receptor agonists rapidly induce specific changes in arachidonic acid and phosphatidic acid metabolism in a glioma cell line and suggest that similar responses may occur in glial cells and play a physiologically significant role in neural metabolism.
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PMID:Cholinergic stimulation of arachidonic acid and phosphatidic acid metabolism in C62B glioma cells. 308 4

Ketoconazole, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, and gossypol are reported inhibitors of the lipoxygenase (LO) and cytochrome P-450 enzyme systems and are potent blockers of swelling-activated efflux of organic osmolytes and volume-sensitive anion channels in C6 glioma cells. To directly test the hypothesis that LO- or cytochrome P-450-derived products of arachidonic acid (AA) participate in the regulation of these volume-sensitive transport pathways, we incubated C6 cells with [1-14C]AA and observed the extent and profile of its conversion under basal conditions and after acute swelling. High-performance liquid chromatographic analysis revealed that most (70-80%) of the labeled AA remained unchanged with only 6-8% and 10-20% of label converted to LO- [12(S)- and 15(S)-hydroxyeicosatetraenoic acid (12- and 15-HETE)] and cyclooxygenase- [prostaglandin (PG) E2 and PGF2a] derived products, respectively. Leukotrienes and epoxyeicosatrienoic acid compounds were not produced. The conversion profile of [1-14C]AA was not altered substantially by cell swelling. Treatment of cells with the LO-derived products 5-, 12-, and 15-HETE or their immediate metabolic precursors, 5(S)-, 12(S)-, and 15(S)-hydroxyperoxyeicosatetraenoic acid, at 5 microM concentrations did not stimulate efflux of [3H]inositol. In addition, treatment with HETEs did not override the inhibition of efflux observed with the LO-cytochrome P-450 blocker ketoconazole. Whole cell patch-clamp experiments demonstrated that volume-sensitive anion channels, the postulated pathway for organic osmolyte efflux in C6 cells, are rapidly and reversibly blocked by ketoconazole in a fashion suggestive of direct inhibition rather than via interruption of a second messenger pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ketoconazole blocks organic osmolyte efflux independently of its effect on arachidonic acid conversion. 751 97

The regulation by intrinsic factors of responses to stress of two small stress proteins, hsp27 and alpha B crystallin, was examined in C6 rat glioma cells. Levels of hsp27 and alpha B crystallin were low in C6 glioma cells in confluent cultures. However, levels of the two proteins increased after exposure of cells to heat (42 degrees C for 30 min) or arsenite (50 microM for 1 h) stress. When cells were exposed to arsenite or hear in the presence of indomethacin (50 microM), an inhibitor of cyclooxygenase, or in the presence of nordihydroguaiaretic acid (NDGA; 50 microM), an inhibitor of lipoxygenase, induction of hsp27 and alpha B crystallin was markedly stimulated as detected by specific immunoassays, Western blot analysis, and Northern blot analysis. The presence of melittin (1 microM), an activator of phospholipase A2, during the stress period also stimulated the induction of the two proteins. The expression of hsp70 to each stress was also enhanced in the presence of indomethacin, NDGA, or melittin. The gel mobility shift assay revealed that these chemicals prolonged the arsenite-induced activation of heat shock element (HSE)-binding activity of heat shock transcriptional factor (HSF) in cells. Induction of hsp27 and alpha B crystallin in adrenal glands of heat-stressed (42 degrees C for 15 min) rats was also enhanced by prior injection of aspirin, another inhibitor of cyclooxygenase. These results indicate that the responses to stress of hsp27 and alpha B crystallin, as well as the response of hsp70, are coupled with the metabolic activity of the arachidonic acid cascade and the mechanism for regulation of stress responses observed in C6 cells is operative in tissues and organs in vivo.
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PMID:Enhancement of stress-induced synthesis of hsp27 and alpha B crystallin by modulators of the arachidonic acid cascade. 859 93

Here, we report that nonsteroidal anti-inflammatory drugs (NSAID) enhance the cytotoxic effects of doxorubicin and vincristine in T98G human malignant glioma cells. The cytotoxicity of BCNU, cisplatin, VM26, camptothecin, and cytarabine is unaffected by NSAID. No free radical formation is induced by doxorubicin or vincristine in the absence or presence of NSAID. Doxorubicin and vincristine cytotoxicity in the absence or presence of NSAID are unaffected by free radical scavengers. Functional inhibitors of phospholipase A2 (PLA2), such as dexamethasone and quinacrine, do not mimick the effects of NSAID. T98G cells, but not LN-18, LN-229, LN-308, or A172 glioma cells, express cyclooxygenase (COX-1) and NSAID do not modulate drug cytotoxicity in the other cell lines, except T98G. Thus, augmentation of doxorubicin and vincristine cytotoxicity by NSAID correlates with COX-1 expression. However, ectopic expression of COX-1 in LN-229 cells does not induce the phenotype of T98G cells, indicating that COX-1 inhibition does not mediate the effects of NSAID on drug cytotoxicity. In contrast, a multidrug resistance (MDR) phenotype due to expression of the multidrug resistance-associated protein (MRP) is most prominent in T98G cells and is amenable to modulation by indomethacin, suggesting that inhibition of MRP is at least in partly responsible for the potentiation of doxorubicin and vincristine cytotoxicity by NSAID.
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PMID:Selective potentiation of drug cytotoxicity by NSAID in human glioma cells: the role of COX-1 and MRP. 1036 64

The induction of Hsp68 by heat shock (HS) and oxidative stress (OS) involves different pathways in C6 rat glioma cells. The pathways were analyzed by specific inhibitors of signal transduction cascades. Quercetin (inhibitor of PLA(2) and lipoxygenase) inhibited only the OS-induced but not the HS-induced expression of Hsp68. Preincubation with quinacrine (inhibitor of PLA(2)) before stress also suppressed the expression of Hsp68 only after oxidative stress. Moreover, another inhibitor of lipoxygenase (alpha-tocopherol) exclusively suppressed OS-induced Hsp68 expression. This different regulation was confirmed by exposing the cells to arachidonic acid (AA) during stress which strongly increased the induction of Hsp68 only after OS. PGE(2) (metabolite of cyclooxygenase) and indomethacin (inhibitor of cyclooxygenase) had no influence on Hsp68 expression in response to both stressors. The results suggest that the induction of Hsp68 by oxidative stress is mainly transmitted by the lipoxygenase pathway in C6 rat glioma cells.
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PMID:Induction of Hsp68 by oxidative stress involves the lipoxygenase pathway in C6 rat glioma cells. 1079 93

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

The capacity of glial tumor cells to migrate and diffusely infiltrate normal brain compromises surgical eradication of the disease. Identification of genes associated with invasion may offer novel strategies for anti-invasive therapies. The gene for TXsyn, an enzyme of the arachidonic acid pathway, has been identified by differential mRNA display as being overexpressed in a glioma cell line selected for migration. In this study TXsyn mRNA expression was found in a large panel of glioma cell lines but not in a strain of human astrocytes. Immunohistochemistry demonstrated TXsyn in the parenchyma of glial tumors and in reactive astrocytes, whereas it could not be detected in quiescent astrocytes and oligodendroglia of normal brain. Glioma cell lines showed a wide range of thromboxane B2 formation, the relative expression of which correlated with migration rates of these cells. Migration was effectively blocked by specific inhibitors of TXsyn, such as furegrelate and dazmegrel. Other TXsyn inhibitors and cyclooxygenase inhibitors were less effective. Treatment with specific inhibitors also resulted in a decrease of intercellular adhesion in glioma cells. These data indicate that TXsyn plays a crucial role in the signal transduction of migration in glial tumors and may offer a novel strategy for anti-invasive therapies.
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PMID:Thromboxane synthase regulates the migratory phenotype of human glioma cells. 1155 Feb 98


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