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)

Suramin is an anti-helminthic drug that has been shown to antagonize the effects of a variety of growth factors including EGF, PDGF and TGF beta. When added to the culture medium, suramin inhibited the proliferation of both human colonic adenocarcinoma cells HT29-D4 and rat glioma cells C6. Suramin also induced the differentiation of both cell lines: appearance of cellular extensions for C6 cells, enterocyte-like epithelial differentiation for HT29-D4-cells. In the latter case, suramin probably acts at the level of glucose metabolism, which is likely to be modulated by autocrine growth factors. The permanent secretion of such factors probably stimulates HT29-D4 proliferation and simultaneously inhibits their differentiation. It is hypothesized that interfering with this autocrine loop, suramin allows HT29-D4 cells to differentiate.
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PMID:[Suramin inhibits the proliferation and stimulates the differentiation of tumoral cell lines HT29-D4 and C6]. 175 32

Suramin is a polyanionic compound currently used under evaluation for antineoplastic activity. One of the main problems encountered during clinical trials was an adverse neurotoxic effect, probably due to a direct cytotoxic effect on neural cells. Suramin is also known to trigger differentiation of human colon cancer cells, yet a chronic treatment induces a lysosomal storage disorder. The aim of this study was to evaluate suramin analogs for their effect: (i) on the lysosomal system of the human colon cancer cell clone HT29-D4; and (ii) on C6 glioma cell growth and morphology. One of the derivatives tested, NF036, induced terminal differentiation of HT29-D4 cells without any impairment of the lysosomal system. Furthermore, in contrast to suramin, NF036 did not alter C6 cell growth and morphology. We conclude that there is a relationship between the ability of a suramin derivative to induce a lysosomal storage disorder in human colon cancer cells and its neurotoxic effect. A double screening of suramin analogs on HT29-D4 and C6 cells allowed us to identify a new candidate antineoplastic drug: NF036.
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PMID:Double screening of suramin derivatives on human colon cancer cells and on neural cells provides new therapeutic agents with reduced toxicity. 175 11

Suramin, a drug used in the treatment of trypanosomiasis and onchocerciasis inhibits growth-factor-induced mitogenesis. We have investigated the effect of suramin on the growth rate and the morphology of C6 glioma cells cultured in the presence of serum or in a serum-free defined medium. Exponentially growing cells were seeded in multi-dish plates (5 x 10(4) cells/2 cm2 well) in DMEM supplemented with 5% fetal calf serum and were continuously exposed to 1 microgram/ml to 1,000 micrograms/ml suramin. Growth rate (determined 9 days after seeding) was reduced by 5%, 33%, 56% and 97%, respectively for suramin concentrations of 1, 10, 100 and 1000 micrograms/ml. Similar results were obtained in serum-free defined medium (DMEM/F12, 1:1, v:v, EGF 5 ng/ml, transferrin 5 micrograms/ml, selenium 10 ng/ml). Moreover, the concentration of suramin in the culture medium remained constant, demonstrating that the drug was not actively metabolized by the cells. Suramin also induced marked changes in cell morphology: the usual bipolar shape of C6 cells evolved toward a more differentiated appearance, with numerous cellular processes allowing a wide number of cell-cell contacts. In parallel, we monitored expression of an adhesion molecule (N-CAM) at both the mRNA and protein levels. Indirect immunofluoresence technique showed an important increase in cell surface N-CAM expression, starting from a dose of 10 micrograms/ml suramin, whereas total cellular content of N-CAM protein as well as its mRNA levels were unaffected. We also observed that the levels of expression of actin and N-CAM mRNAs decreased by a factor of two in cells maintained in defined medium. However, the relative ratio of N-CAM mRNA over actin mRNA was virtually unchanged following suramin treatment. Taken together, our results suggest that suramin (i) exerts a blocking effect of autocrine growth factors, (ii) interferes with the turn-over mechanisms of N-CAM expressed at the cell surface, either by impairing its endocytosis and/or the process of release of the N-CAM 120 isoform.
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PMID:Suramin inhibits proliferation of rat glioma cells and alters N-CAM cell surface expression. 230 43

The anti-helminthic drug suramin inhibited the basal high-affinity GTPase activity of both C6 BU1 glioma and NG 108-15 neuroblastoma x glioma hybrid-cell membranes with an IC50 (concentration causing half-maximal inhibition) value close to 30 micrograms/ml. This effect was shown to occur via a non-competitive mechanism in which the binding affinity of the G-proteins for GTP was not altered, but the maximal velocity of the subsequent hydrolysis was reduced. In NG 108-15 membranes, both opioid peptides and foetal-calf serum stimulated high-affinity GTPase activity in a pertussis-toxin-sensitive manner. These effects have previously been shown to be mediated by different G-proteins [McKenzie, Kelly, Unson, Spiegel & Milligan (1988) Biochem. J. 249, 653-659]. Suramin completely prevented the opioid-peptide-stimulated increase in GTP hydrolysis, but did not prevent the opioid peptide from binding to its receptor. Suramin, however, did not block the foetal-calf-serum-stimulated GTPase response. This selective action of suramin provides further evidence for distinct roles for two separate pertussis-toxin-sensitive G-proteins in signal transduction in NG 108-15 membranes and provides the first evidence for a selective effect of a drug on the functions of different G-proteins.
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PMID:Differential effects of suramin on the coupling of receptors to individual species of pertussis-toxin-sensitive guanine-nucleotide-binding proteins. 283 58

Suramin, a non-specific growth factor antagonist, has been reported to have pleiotrophic action on the proliferation of some kinds of tumours and has therefore attracted attention as an agent in the treatment of cancer. We studied its action on human glioma cell lines in vitro by examining the effect of suramin on the proliferation and the cell cycle and mitogen-activated protein (MAP)-kinase activity of glioma cells. We found that at low concentration (50, 100 micrograms/ml) suramin had a stimulatory effect while at higher concentrations (200, 500 micrograms/ml) it had an inhibitory effect on the proliferation of 4 human glioma cell lines. At low concentrations, suramin stimulated the transition of glioma cells from a quiescent state (G0) to the proliferative phase (S phase); MAP kinase activity was also increased. The stimulatory effect of low concentrations of suramin on the proliferation of glioma cells may have important consequences for glioma patients treated with suramin.
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PMID:Stimulatory effect of suramin on the proliferation of human glioma cells. 765 6

Suramin is a novel anticancer agent that blocks the binding of growth factors, including basic fibroblast growth factor (bFGF), to their receptors. Prior studies showed human and experimental gliomas to upregulate and respond to autocrine stimulation by bFGF, the antiproliferative effects of suramin were therefore studied on glioma cell turnover in vitro and in the brain. Suramin inhibited the growth of rat (C6, 9L) and human (U-118, U-138, A-172, T98G) glioma cell lines in a dose-dependent manner. Suramin significantly reduced the bromodeoxyuridine (BUdR) labeling index of cultured glioma cells at 250 micrograms/ml, P < 0.0001. DNA flow cytometry revealed a significant decrease in the percentage of suramin-treated glioma cells in S-phase, P < 0.01. Using intracerebral rat C6 glioma model in vivo, suramin, 10-60 mg/kg, i.p., produced a dose-dependent reduction of BUdR labeling in both the glioma and endothelial cell subpopulations. Suramin, 200 mg/kg i.v., however, led to intratumoral hemorrhages that reduced survival. Electron microscopy revealed membranous inclusion bodies in the cytoplasm of C6 glioma and endothelial cells, an indication of excess glycosaminoglycans. Moreover, 46% of endothelial cells within the C6 glioma tumor treated with suramin, 60 mg/kg, i.p., developed membrane blebs. Suramin, in clinically relevant doses, significantly inhibits glioma cell growth and cytokinetics. The risk of intratumoral hemorrhage, possibly related to injury of endothelial cells or the accumulation of anticoagulant glycosaminoglycans, constitutes a major side effect and caution should be exercised in consideration of clinical application for intracerebral tumors.
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PMID:Suramin inhibits glioma cell proliferation in vitro and in the brain. 769 15

1. Stimulation of P2Y-purinoceptors on turkey erythrocytes and many other cell types results in activation of phospholipase C. In contrast, we have observed recently that P2Y-purinoceptors on C6 rat glioma cells are not coupled to phospholipase C, but rather, inhibit adenylyl cyclase. 2. In this study we investigated the pharmacological selectivity of the P2-purinoceptor antagonists, suramin, reactive blue 2, and pyridoxal phosphate 6-azophenyl 2',4'-disulphonic acid (PPADS) for phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors. 3. In C6 glioma cells, suramin and reactive blue 2 competitively antagonized the inhibitory effect of 2MeSATP on adenylyl cyclase (pKB = 5.4 +/- 0.2 and 7.6 +/- 0.1, respectively), whereas PPADS at concentrations up to 100 microM had no effect. 4. In contrast, in the turkey erythrocyte preparation, PPADS at concentrations up to 30 microM was a competitive antagonist of P2Y-purinoceptor-stimulated phospholipase C activity (pKB = 5.9 +/- 0.1). Suramin and reactive blue 2 produced both a shift to the right of the concentration-effect of 2MeSATP for the activation of phospholipase C and a significant decrease in the maximal inositol phosphate response. 5. Turkey erythrocytes also express a phospholipase C-coupled beta-adrenoceptor. Concentrations of PPADS that competitively inhibited the P2Y-purinoceptor-mediated response had only minimal effects on the activation of phospholipase C by beta-adrenoceptors. In contrast, suramin and reactive blue 2 produced a non-competitive inhibition, characterized by decreases in the maximal response to isoprenaline with no change in the potency of this beta-adrenoceptor agonist. 6. The differential effect of PPADS on P2Y-purinoceptors of C6 glioma cells and turkey erythrocytes adds further support to the idea that different P2Y-purinoceptor subtypes mediate coupling to adenylylcyclic and phospholipase C.
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PMID:Differential effects of P2-purinoceptor antagonists on phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors. 783 15

In C6 glioma cells, extracellular ATP and other nucleotide analogs stimulated phosphoinositide (PI) breakdown and inhibited isoproterenol-induced cyclic AMP (cAMP) accumulation. The rank orders of potencies of 15 nucleotide analogs for both responses were clearly different. ATP and adenosine 5'-O-(3-thiotriphosphate) are the most potent agonists for stimulating PI hydrolysis; 2-methylthio-ATP (2-MeSATP) is the most potent agonist for inhibiting cAMP accumulation. P1-mediated responses of PI turnover and cAMP formation are not present in C6 glioma cells. Pertussis toxin (PTX) blocked the nucleotide-induced inhibition of cAMP accumulation but exerted no effect on inositol phosphate formation. Short-term treatment with phorbol 12-myristate 13-acetate inhibited both signal transduction pathways. The effects of three P2 purinergic antagonists, suramin, reactive blue and 4,4'-diisothiocyanatostilbene sulfonic acid (DIDS), on ATP- and 2-MeSATP-induced stimulation of PI turnover and inhibition of cAMP formation, respectively, were compared. For stimulating PI turnover, suramin is a competitive antagonist (pA2, 4.4); reactive blue and DIDS are noncompetitive antagonists at 30 microM and 100 microM, respectively. For the inhibition of cAMP formation, reactive blue and DIDS competitively antagonized the response of 2-MeSATP (pA2 values, 6.3 for reactive blue and 5.7 for DIDS); suramin was only slightly effective at 100 microM. It was concluded that the nucleotide receptor is linked to phospholipase C by a PTX-insensitive Gp protein and the P2Y receptor is linked to adenylyl cyclase by a PTX-sensitive Gi protein. Suramin is a competitive antagonist for the nucleotide receptor; reactive blue and DIDS are more selective antagonists for the P2Y receptor.
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PMID:Different signal transduction pathways are coupled to the nucleotide receptor and the P2Y receptor in C6 glioma cells. 801 79

Tumor cells of glial origin express high levels of basic fibroblast growth factor (bFGF) which stimulates their proliferation in an autocrine manner. In the present study we examined bFGF receptor (FGFR) expression and 125I-bFGF binding and processing in a human glioma cell line. RT-PCR demonstrated the co-expression of bFGF and FGFR mRNAs in five glioma cell lines examined. The high-affinity FGFR was visualized in U87-MG glioma cells by crosslinking with 125I-bFGF and by Western blotting with anti-receptor antisera. Both techniques identified a discrete 110-kDa moiety associated with the cell membrane, consistent with the reported size of one of the FGFR-1 isoforms. Western blotting also identified an intracellular receptor pool which was not accessible with exogenous 125I-bFGF. Suramin treatment induced a 2-fold increase in immunoreactive FGFR and a 1.5-fold increase in 125I-bFGF binding sites, indicating that FGFRs are chronically down-regulated by endogenous bFGF in U87-MG cells. Removal of extracellular bFGF with heparin resulted in a rapid, cycloheximide-sensitive increase in high-affinity bFGF binding sites. At 37 degrees C, receptor-bound 125I-bFGF was internalized and subjected to limited proteolytic cleavage over 12 h. U87-MG cells also contained abundant low-affinity bFGF binding sites which were removed by digestion with heparinase III but not by chondroitinase ABC. The presence of heparin (25 micrograms/ml) in the binding reaction eliminated the association of 125I-bFGF with the heparin-like sites but did not prevent binding to the high-affinity receptor. Scatchard binding analysis in the presence of heparin revealed a single class of high-affinity sites in U87-MG cells (Kd = 4.9 +/- 0.9 pM; 10-12 x 10(3) sites per cell). Neither heparin nor heparinase digestion prevented the binding of 125I-bFGF to the detergent-extractable high-affinity receptor, although both treatments significantly reduced the extent of 125I-bFGF association with the receptor. These findings indicate that in U87-MG cells, heparan sulfate proteoglycans may be involved in presentation of bFGF to the high-affinity receptor, but are not essential for high-affinity binding to occur.
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PMID:Basic fibroblast growth factor binding and processing by human glioma cells. 867 45

1. In glioma C6 cells, the stimulation of P2Y receptors by ADP, ATP and UTP initiated an increase in the intracellular Ca2+ concentration, in a process that involved the release of Ca2+ from InsP(3)-sensitive store and the capacitative, extracellular Ca2+ entry. The presence of external Ca2+ was not necessary to elevate Ca(2+). 2. The rank order of potencies of nucleotide analogues in stimulating [Ca2+](i) was: 2MeSADP > ADP > 2MeSATP = 2ClATP > ATP > UTP. alpha,beta-Methylene ATP, adenosine and AMP were ineffective. 3. ADP and UTP effects were additive, while actions of ATP and UTP were not additive on [Ca2+](i) increase. Similarly, cross-desensitization between ATP and UTP but not between ADP and UTP occurred. 4. Suramin, a non-specific nucleotide receptors inhibitor, antagonized ATP-, UTP- and ADP-evoked Ca2+ responses. PPADS, a selective antagonist of the P2Y(1) receptor-generated InsP(3) accumulation, decreased ADP-initiated Ca2+ response with no effect on ATP and UTP. 5. Pertussis toxin (PTX) reduced ADP- and ATP-induced Ca2+ increases. Short-term treatment with TPA, inhibited both ATP and ADP stimulatory effects on [Ca2+](i). 6. ADP inhibited isoproterenol-induced cyclic AMP accumulation. PTX blocked this effect, but PPADS did not. 7. RT - PCR analysis revealed the molecular identity of P2Y receptors expressed by glioma C6 cells to be both P2Y(1) and P2Y(2). 8. It is concluded that both P2Y(1) and P2Y(2) receptors co-exist in glioma C6 cells. ADP acts as agonist of the first, and ATP and UTP of the second one. Both receptors are linked to phospholipase C (PLC).
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PMID:Two subtypes of G protein-coupled nucleotide receptors, P2Y(1) and P2Y(2) are involved in calcium signalling in glioma C6 cells. 1115 87


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