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)

Recent data have suggested that mitochondria play a supportive role in maintaining the tumorigenic phenotype. Indeed, antimitochondrial agents have been hypothesized to be potential chemosensitizers to human malignancy. We assessed the utility of this approach by characterizing the antimitochondrial activity of 3,5-di-tert-butyl-4-hydroxybenzylidene-malononitrile (AG17), in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in two human glioblastoma cell lines. AG17 (NSC 242557) is a tyrphostin that has been thought to have some antimitochondrial activity, with limited tyrosine kinase antagonism, and was used at noncytotoxic and nongrowth-inhibitory concentrations (0.25 microM). Glioblastoma cells were incubated in AG17, and changes in mitochondrial activity were determined. Tumor cells became auxotrophically dependent on uridine and pyruvate, indicating the lack of a functioning respiratory chain. Despite this, cells continued to exhibit no growth-inhibitory effects. Exposure to AG17 was associated with significant depolarization of the mitochondrial membrane potential and decreases in mitochondrial mass in both glioblastoma cell lines, correlating with the finding of auxotrophic dependence. In contrast, normal human astrocytes treated with the same dose of AG17 did not show changes in growth, mitochondrial membrane potential, or mass. Indeed, auxotrophic dependence on uridine and pyruvate could not be established in these cells. Glioblastoma cells became significantly more responsive to BCNU chemotherapy with AG17 pretreatment; a linear relationship was noted that correlated the number as well as percentage of polarized mitochondria with glioblastoma cell survival at the highest dose of BCNU used (144 microg/ml). Normal human astrocytes did not change with regard to the dose response to BCNU with previous incubation with AG17. No difference was found in the type of cellular death (apoptosis) in either of the glioblastoma cell lines, with BCNU treatment alone, or with the combination AG17 and BCNU, despite the decrease in polarized mitochondria and mitochondrial mass. AG17 has antimitochondrial properties when used at low dose in human glioblastoma, which are relatively specific to tumor cells when compared with normal astrocytes. The use of AG17 as a chemosensitizer, with drugs such as BCNU, offers a new and possibly effective approach to be developed in patients with glial tumors.
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PMID:Chemosensitization of glioblastoma cells to bis-dichloroethyl-nitrosourea with tyrphostin AG17. 953 47

Glioblastoma multiforme is a malignant primary brain tumor associated with short patient survival in part because of the ability of individual cells to migrate significant distances into brain tissue. Invasion is a difficult process to model, because many such human tumors do not invade immunologically competent animal tissue, tumors grown in animals do not invade human tissue, and relevant human tissue substrates are not easily reproduced. We discuss models for examining invasion in vitro, and in particular review work using the tumor spheroid--fetal rat brain aggregate co-culture model, assessed with confocal microscopy and four-dimensional imaging. Quantitation of invasion in this model is discussed, as well as the invasion-inhibitory properties of tyrosine kinase (TK) inhibitors. The effects of receptor-specific tyrphostins strongly support a dominant role for Epidermal Growth Factor Receptor activation in this process and show that invasion can be effectively inhibited at much lower concentrations of TK inhibitors than is necessary for growth suppression. Inhibition of activation of the purported growth factor receptor second messenger phospholipase C- gamma 1, by pharmacological means and gene transfection, also profoundly inhibits the invasive properties of human glioblastoma and rat C6 glioma cells. We have assessed invasiveness in several human tumor specimens, which may provide information relative to prognosis and recurrence risk. Our data supports the concept of differential control of invasion and proliferation, and points to possible strategies for anti-invasive therapy for glioblastoma multiforme.
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PMID:Inhibition of glioma invasion of fetal brain aggregates. 957 29

The effects of genistein and erbstatin analogue, inhibitors of tyrosine kinase, on Ca2+ mobilization evoked by thapsigargin (TG) were examined in rat glioma C6 cells. Genistein and erbstatin analogue inhibited the Ca2+ release from intracellular pools as well as Ca2+ entry from extracellular medium evoked by TG in a dose-dependent manner. However, they did not affect a Ca2+ entry due to leakage of Ca2+ from extracellular medium into cells. The present results suggest that tyrosine kinase inhibitors inhibit capacitative Ca2+ entry due to the inhibition of both Ca2+ entry itself and Ca2+ release in rat glioma C6 cells.
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PMID:Inhibitory effects of tyrosine kinase inhibitors on capacitative Ca2+ entry in rat glioma C6 cells. 958 75

The effect of stress on the production of cytokine-induced neutrophil chemoattractant (CINC) was examined in rat C6 glioma cells. We studied the production of CINC, an interleukin-8 (IL-8) family protein, with bacterial endotoxin, H2O2, and tumor necrosis factor-alpha (TNF-alpha). Each stress induced CINC mRNA in a concentration-dependent manner. Since stress activates the protein kinases regulating nuclear transcription factors, we examined the effects of protein kinase inhibitors and the over-expression of dominant-negative Ras on CINC mRNA expression. Neither over-expression of dominant-negative Ras nor pretreatment with PD98059 (MEK-1 inhibitor), SB203580 (p38MAPK inhibitor), or GF109203X (protein kinase C (PKC) inhibitor) altered stress-induced CINC mRNA expression. This suggests that the Ras-MAPK, p38MAPK, and PKC pathways are not involved in CINC mRNA expression in glial cells. On the other hand, pretreatment with herbimycin A, a potent tyrosine kinase inhibitor, or Ro31-8220, a non-selective serine/threonine kinase inhibitor, suppressed stress-induced CINC mRNA expression. This indicates that stress-induced CINC mRNA expression is mediated by herbimycin A-, or Ro31-8220-sensitive kinases in glial cells. Since stress activates NF-kappaB and NF-IL6, we examined that the effect of herbimycin A, which suppresses CINC mRNA expression, on NF-kappaB and NF-IL6 activation. Herbimycin A suppressed NF-kappaB but not NF-IL6. These results suggest that in rat glial cells, the factors that induce CINC mRNA expression are mediated by herbimycin A-sensitive NF-kappaB activation, but not through the PKC, Ras-MAPK or p38 MAPK pathways.
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PMID:Induction of cytokine-induced neutrophil chemoattractant in response to various stresses in rat C6 glioma cells. 959 44

Amplification and rearrangement of the epidermal growth factor receptor (EGFR) gene occur frequently in malignant gliomas. Rearrangement may also lead to the expression of potentially oncogenic EGFR deletion mutants. Data presented here indicate the existence of a 190 kDa mutant form of the EGFR in A-172 glioma cells that is substantially different from the deletion mutants characterized previously. The EGFR-like protein is expressed along with the 170 kDa wild type EGFR. It is detectable with antibodies to both extracellular and intracellular regions of the EGFR, but is not crossreactive with other HER-family members. The wild type and mutant receptors undergo phosphorylation in response to treatment with TGFalpha and are associated with expression of both 10.5 kb and 11.5 kb EGFR-related transcripts. Combined reverse transcription-polymerase chain reaction (RT-PCR) identifies a unique transcript in A-172 cells that encodes an in-frame, tandem duplication of both tyrosine kinase and calcium internalization (TK/CAIN) domains (exons 18 through 26). The duplication of these domains is associated with a specific genomic rearrangement between potential v-myb and c-myb consensus binding sites within introns 26 and 17 of the EGFR gene resulting in the formation of a chimeric intron.
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PMID:Tandem duplication of the epidermal growth factor receptor tyrosine kinase and calcium internalization domains in A-172 glioma cells. 969 51

Drugs that influence tubulin function were used to investigate the role of microtubules in hexose uptake by C6 glioma cells. In C6 cells, colchicine and vinblastine (which inhibit tubulin polymerization) inhibited radioactive [3H]2-deoxy-D-glucose uptake by about 30%. Paclitaxel (which promotes tubulin polymerization) stimulated hexose uptake by about 25%. To further demonstrate that microtubules play a role in hexose uptake, C6 cells were transfected with GLUT1 cDNA and then challenged with 100 nM paclitaxel. In GLUT1-transfected cells paclitaxel stimulated 2-deoxy-D-glucose uptake by about 35%. To study the role of tubulin in agonist-stimulated hexose uptake, the effect of colchicine on carbachol-induced uptake was next examined. Hexose uptake was increased with carbachol in concentration-dependent manner which was abolished by pretreatment with colchicine. To examine the specificity of the inhibitory effect of colchicine on G protein-mediated signal transduction pathway, the influence of colchicine on insulin (which acts via tyrosine kinase pathway) stimulation of 2-deoxy-D-glucose uptake was investigated. Hexose uptake was increased by insulin in a concentration-dependent manner which was unaffected by pretreatment with colchicine. These results suggest that microtubules are involved in basal and carbachol-stimulated glucose uptake by C6 cells.
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PMID:Role of microtubules in glucose uptake by C6 glioma cells. 978 25

Growth factors are known to regulate glioma proliferation. The glioma cell lines U87 and T98G were examined for evidence of an autocrine stimulatory loop involving the neurotrophin family of growth factors. Although neurotrophin-3 and TrkC RNA were detected by reverse transcription-PCR, there was no evidence of significant interaction between neurotrophin-3 and its cognate receptor TrkC. The microbial alkaloid K252a has been described to inhibit both Trk tyrosine kinase activity and neuroblastoma cell proliferation. K252a inhibited proliferation in U87 (IC50 = 1170 nM) and T98G (IC50 = 529 nM) but induced apoptosis in U87 cells only. At concentrations of 500 nM to 1 microM, K252a blocked only platelet-derived growth factor (PDGF)-mediated receptor autophosphorylation. These results suggest that an autocrine loop involving PDGF is functional and important for maintaining tumor growth. There is no evidence to support the existence of a neurotrophin-mediated autocrine loop. K252a, through inhibition of PDGF signal transduction, may be a novel therapeutic agent in the treatment of human gliomas.
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PMID:K252a inhibits proliferation of glioma cells by blocking platelet-derived growth factor signal transduction. 981 48

Epidermal growth factor receptor (EGFR) plays an important role in the progression of malignancy in gliomas. We studied the growth inhibition of the malignant glioma cell lines using an antisense EGFR oligodeoxynucleotide enveloped with Lipofectin. At a concentration of 5 microM of the antisense EGFR oligodeoxynucleotide enveloped with Lipofectin, the proliferation of three malignant glioma cell lines was significantly inhibited (p < 0.05) compared with that of the cells exposed to 5 microM sense EGFR oligodeoxynucleotide. The activity of the tyrosine kinase and the DNA synthesis was also significantly suppressed (p < 0.05). These findings show that the antisense EGFR oligodeoxynucleotide enveloped with Lipofectin has a possibility to become a useful gene therapy against malignant gliomas.
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PMID:An antisense EGFR oligodeoxynucleotide enveloped in Lipofectin induces growth inhibition in human malignant gliomas in vitro. 982 Nov 9

In this study, simultaneous administration of certain inhibitors of topoisomerase I and topoisomerase II produced synergistic cytotoxicity in a series of human glioma cell lines. Camptothecin (CPT) and etoposide (VP-16) produced combination indices (CI) <1.0 in all glioma cell lines tested, including those that were relatively resistant to the two topoisomerase inhibitors individually. In contrast, CPT and VP-16 produced additive cytotoxicity in HT-29 and SW-620 colon carcinoma cell lines. To explore the molecular basis for synergy in glioma cells, we focused on one glioma cell line (U87) in which even sub-cytotoxic doses of CPT potentiated the action of VP-16. Except for genistein (a topo II agent with tyrosine kinase inhibitory function), all topo II inhibitors tested (doxorubicin, ellipticine, and m-AMSA) were synergistic with CPT. While CPT and VP-16 produced cytotoxicity and protein-linked DNA breaks (PLDB) that were supra-additive in U87 glioma cells, CPT and genistein produced additive results. Pretreatment of U87 cells with the tyrosine kinase inhibitor tyrphostin-A23 or the tyrosine phosphatase activator O-phospho-L-tyrosine (OPLT) reduced combination PLDB from synergistic to additive levels, but had no effect on the formation of PLDB induced by either CPT or VP-16 alone. CPT and VP-16 also produced a synergistic accumulation of sub-G0 (apoptotic) cells which was blocked by tyrphostin-A23. No significant increase in topoisomerase protein levels could be detected in response to combination treatment. Thus, synergistic effects between topoisomerase I and topoisomerase II inhibitors in U87 glioma cells may depend upon phosphorylation of cellular proteins other than the topoisomerases themselves.
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PMID:Synergistic cytotoxicity, apoptosis and protein-linked DNA breakage by etoposide and camptothecin in human U87 glioma cells: dependence on tyrosine phosphorylation. 1035 42

Leflunomide, a novel immunomodulatory drug, has two biochemical activities: inhibition of tyrosine phosphorylation and inhibition of pyrimidine nucleotide synthesis. In the present study, we first showed that A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], the active metabolite of leflunomide, was more effective at inhibiting the tyrosine kinase activity of platelet-derived growth factor (PDGF) receptor than that of epidermal growth factor (EGF) receptor, and had no effect on the tyrosine kinase activity of the fibroblast growth factor receptor. In the presence of exogenous uridine, A77 1726 was more effective at inhibiting the PDGF-stimulated proliferation of PDGF receptor-overexpressing C6 glioma than the EGF-stimulated proliferation of EGF receptor-overexpressing A431 cells. In vivo studies demonstrated that leflunomide treatment strongly inhibited the growth of the C6 glioma but had only a modest effect on the growth of the A431 tumor. Uridine co-administered with leflunomide did not reverse the antitumor activity of leflunomide on C6 and A431 tumors significantly. Quantitation of nucleotide levels in the tumor tissue revealed that leflunomide treatment significantly reduced pyrimidine nucleotide levels in the fast-growing C6 glioma but had no effect on the relatively slow-growing A431 tumor. Whereas uridine co-administration normalized pyrimidine nucleotide levels, it had minimal effects on the antitumor activity of leflunomide in both tumor models. Immunohistochemical analysis revealed that leflunomide treatment significantly reduced the number of proliferating cell nuclear antigen-positive cells in C6 glioma, and that uridine only partially reversed this inhibition. These results collectively suggest that the in vivo antitumor effect of leflunomide is largely independent of its inhibitory effect on pyrimidine nucleotide synthesis. The possibility that leflunomide exerts its antitumor activity by inhibition of tyrosine phosphorylation or by a yet unidentified mode of action is discussed.
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PMID:In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action. 1051 84


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