Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear proteins obtained from human brain tumor cell lines by differential salt extraction were subjected to high-resolution two-dimensional electrophoresis. Several hundred spots were detectable in the low salt (0.4 M NaCl) extract using silver staining. These patterns exhibited remarkable differences between the different cell lines we analyzed. A less complex pattern occurred when nuclei were subsequently treated with high salt (2.5 M NaCl/5 M urea). We compared the electropherograms from various human glioblastoma cell lines and found them very similar and even a high degree of similarity occurs between glioblastomas and other human tumor cell lines. Beside these more general observations we detected several proteins at least enriched in human glioblastomas which were totally absent in low grade astrocytomas and nonglial tumors. They could be separated from the bulk of nonspecific proteins by simple modifications of the isoelectric focusing conditions. From these results we conclude that nuclear proteins obtained by sequential salt extraction and separated by two-dimensional techniques may provide tumor specific proteins suitable for antibody production.
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PMID:Nuclear and DNA-binding proteins in human brain tumors. 191 44

Hexabrachions are extracellular proteins expressed in certain tissues and at specific points in development. cDNA sequencing has revealed that they contain a region of repeats that are similar to the type III homology units of fibronectin. The corresponding region of fibronectin contains heparin- and DNA-binding domains. We have compared the heparin and DNA binding of hexabrachion secreted by the human glioblastoma cell line U87MG to that of fibronectin. Both proteins bound to heparin-agarose in low salt (0.05 M NaCl) buffers. Using linear salt gradients, hexabrachion was eluted from heparin prior to fibronectin. The addition of 5 mM CaCl2 decreased the affinity of both proteins for heparin, but it had a greater effect upon the binding of fibronectin. Free heparin but not chondroitin sulfate inhibited the binding of both proteins to heparin-agarose. In addition, hexabrachion bound to DNA as fibronectin does, and this binding could be inhibited by heparin but not by chondroitin sulfate. Unlike fibronectin, hexabrachion did not bind to gelatin when samples containing both proteins were passed over gelatin-agarose, also indicating that there was no interaction between hexabrachion and fibronectin. In contrast to hexabrachion isolated from brain, the protein secreted by the human glioblastoma cell line U87MG does not bear the HNK-1 epitope which is on a carbohydrate that can mediate interactions between cells.
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PMID:Binding of hexabrachions to heparin and DNA. 247 87

C6 rat glioblastoma cells are able to attach to and to spread on culture dishes which are coated with purified central nervous system myelin, in contrast to normal astrocytes, fibroblasts or neurons which adhere poorly and are unable to spread on this substrate. The metalloprotease blockers o-phenanthroline and a newly developed oligopeptide could specifically inhibit C6 cell spreading on central nervous system myelin, suggesting a crucial role for a metalloprotease. Here we characterize this metalloproteolytic activity of C6 cells using a peptide degradation assay with the iodinated tetrapeptide carbobenzoxy-Phe-Ala-Phe-125I-Tyr-amide as a substrate. Purified, salt-washed C6 plasma membranes cleaved the peptide between alanine and phenylalanine, an effect which is strongly inhibited by o-phenanthroline, but not by thiol-blocking agents or aspartic and serine protease inhibitors. The metalloendoprotease is highly sensitive to phosphoramidon but insensitive to thiorphan. The enzyme is tightly bound to the plasma membrane but not G protein-phosphatidylinositol linked. It can be solubilized in part by the detergents 3-(3-cholamidopropyldimethylamino)-1-propanesulfonate or Triton X-114. Gel filtration chromatography using the Triton X-114-solubilized proteins or the proteins removed by a short trypsin treatment revealed a molecular weight range for the C6 enzyme of 60,000-100,000. Polymerase chain reaction with primers corresponding to endopeptidase 24.11 or to the highly conserved motif of the "astacin family" showed that both enzymes were not detectable in the C6 glioblastoma cells.
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PMID:Characterization of a membrane-bound metalloendoprotease of rat C6 glioblastoma cells. 803 33

Malignant gliomas, the most common form of primary brain tumors, are highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical to cell replication. Human glioblastoma cells were found to be uniquely vulnerable to growth arrest by lovastatin, a competitive inhibitor of the enzyme regulating MVA synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. The sodium salt of phenylacetic acid (NaPA), an inhibitor of MVA-pyrophosphate decarboxylase, the enzyme that controls MVA use, acted synergistically with lovastatin to suppress malignant growth. When used at pharmacologically attainable concentrations, the two compounds induced profound cytostasis and loss of malignant properties such as invasiveness and expression of the transforming growth factor-beta 2 gene, coding for a potent immunosuppressive cytokine. Supplementation with exogenous ubiquinone, an end product of the MVA pathway, failed to rescue the cells, suggesting that decreased synthesis of intermediary products are responsible for the antitumor effects observed. In addition to blocking the MVA pathway, lovastatin alone and in combination with NaPA increased the expression of the peroxisome proliferator-activated receptor, a transcription factor implicated in the control of lipid metabolism, cell growth, and differentiation. Our results indicate that targeting lipid metabolism with lovastatin, used alone or in combination with the aromatic fatty acid NaPA, may offer a novel approach to the treatment of malignant gliomas.
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PMID:Lipid metabolism as a target for brain cancer therapy: synergistic activity of lovastatin and sodium phenylacetate against human glioma cells. 859 43

Sodium-L-ascorbate, L-ascorbic acid, D-isoascorbic acid, sodium 5,6-benzylidene-L-ascorbate and sodium-6-beta-O-galactosyl-L-ascorbate, which produce ascorbyl radicals during the oxidative degradation, also induced cytotoxicity against cultured human renal carcinoma (TC-1) and glioblastoma multiform tumor (T98G) cell lines. On the other hand, L-ascorbic acid 2-phosphate magnesium and L-ascorbic acid 2-sulfate dipotassium salt, which do not produce the ascorbyl radical, were inactive. This suggests the possible role of the ascorbyl radical for cell death induction. T98G cells were more resistant to ascorbate analogs than TC-1 and HL-60 cells, possibly due to higher intracellular glutathione concentrations. Ascorbate treatment induced rapid elevation of both intracellular concentration of cAMP and Ca2+ in HL-60 cells, but not in TC-1 and T98G cells. However, the elevation of cAMP by theophyline and N,2-dibutyryl adenosine 3,5 cyclic monophosphate (dibutyryl cAMP) resulted in a decrease in the viable cell number. This suggests the possible role of cAMP for ascorbate-induced cell death.
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PMID:Induction of cell death by ascorbic acid derivatives in human renal carcinoma and glioblastoma cell lines. 1065 1

Reactive oxygen species are toxic and cancerogenic factors to living organisms. They are suggested to cause DNA damage (modification) that triggers cancer development. It seems that oxidative damage product 8-oxo-deoxyguanosine (8-oxo-dG) which induces transversion of G to T could be a good chemical marker for cancerogenesis. The aim of our studies was to use 8-oxo-dG as a probe for brain tumour in 17 patients operated on for intracranial neoplasm. Among the patients there were 7 female and 11 male aged from 14 to 60 year. Mean age was 42.88 +/- 16.14 yrs. Several types of tumours were selected histopathologically: from neuroepithelial tissue--6 cases, meningeomas--4, metastases--3, lymphomas--2, neurinoma--1 and chondrosarcoma--1. The tumour tissue was collected from removed material and stored at -20 degrees C. DNA from the neoplastic tissues was isolated by salt method. After hydrolysis of DNA with nuclease P1 and dephosphorylation with bacterial alkaline phosphatase, the mixture of nucleosides was analysed by liquid chromatography method connected with electrochemical detector (HPLC-ECD) working at potential 400 mV. We found higher level of 8-oxo-dG in DNA of patients with malignant tumour (glioblastoma). However, at the present stage of these studies there was no proportional correlation between the level of 8-oxo-dG in DNA in tumour tissue and its malignancy.
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PMID:[8-oxoguanosine as a marker of neoplastic process in brain]. 1079 Oct 36

Ras activation occurs through stimulation of an upstream growth factor receptor such as epidermal growth factor receptor (EGFR). The ultimate effect of Ras is to induce nuclear transcription via a signaling pathway sequentially involving Raf, MAP kinase kinase (MEK), and mitogen-activated protein kinase (MAPK). To transform cells, Ras oncoproteins must be posttranslationally modified with a farnesyl group in a reaction catalyzed by farnesyl protein transferase. Farnesyltransferase inhibitors, therefore, have been proposed as potent anticancer agents. This study demonstrates the growth-inhibitory effects of farnesyltransferase inhibitor SCH66336 on human glioblastoma cell lines U-251 MG, U-251/E4 MG (a stably transfected cell line with elevated EGFR expression), and U-87 MG. As determined by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) and viability assays, the concentration required to achieve 50% inhibition (IC50) ranged from 30 microM (single 24-h treatment) to 10 microM (5-day treatment). U-251/E4 MG with overexpression of EGFR were more sensitive than U-251 MG parental cells. These observations were also supported by soft agar analysis. Cells treated with SCH66336 underwent G2 arrest. Western blot analysis revealed a decrease in phospho-MAPK levels upon treatment with 10 microM SCH66336, whereas MAPK levels were unaffected by the drug. Interestingly, increased expression of EGFR was observed in U-251 MG and U-251/E4 MG but not in U-87 MG in the presence of the inhibitor. These results demonstrate that SCH66336 inhibits viability and anchorage-independent growth in a time- and dose-dependent manner in glioblastoma cell lines U-251 MG, U-251/E4 MG, and U-87 MG via a signal transduction pathway involving the down-regulation of phospho-MAPK. Overexpression of EGFR appears to alter cellular sensitivity to farnesyltransferase inhibitors. This may have a particularly important implication in glioblastoma, where over 50% of tumors have amplification and overexpression of EGFR.
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PMID:Inhibition of cell growth in human glioblastoma cell lines by farnesyltransferase inhibitor SCH66336. 1130 35

Aluminum is highly oxophilic and its minerals are usually found surrounded by six oxygen atoms. A role for the metal has been established in dialysis encephalopathy and Al-induced osteomalacia. The metal has been implicated in Alzheimer's disease but the issue is at present controversial. Human cell lines of neural origin were utilized to study the effect of lipophilic aluminum acetylacetonate and non-lipophilic aluminum sulfate on cell proliferation and viability. Although analysis of Al species in the cell culture media demonstrated that there are positively charged Al species present in solutions prepared with both Al salts, only the aluminum acetylacetonate salt caused changes in cell proliferation and viability. Therefore, the lipophilic nature of the organic Al salt is a critical determinant of toxicity. The effect of aluminum acetylacetonate was dose-dependent and time-dependent. Neuroblastoma (SK-N-SH) cells were more susceptible to decreased cell proliferation although the lipophilic Al salt was more toxic to the glioblastoma (T98G) cells. While the toxicity of aluminum acetylacetonate was inhibited in the T98G cells by the addition of phosphate, the same treatment did not reverse cell death in the SK-N-SH cells. Thus, the mechanism of Al toxicity appears to be different in the two cell lines. It is possible that the principal neurotoxic target of the metal is glial and when these cells are in a compromised state, this may secondarily impact the neuronal population and thus eventually lead to neurodegeneration.
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PMID:Differential toxicity of aluminum salts in human cell lines of neural origin: implications for neurodegeneration. 1130 52

CI-1033 (N-[4-[N-(3-chloro-4-fluorophenyl)amino-7-[3-(4-morpholynyl)propoxy]quinazolin-6-yl]acrylamide, PD 0183805-mesylate salt) was identified as a potent, selective inhibitor of erbB family tyrosine kinases, which are overexpressed in a number of solid tumors and have been shown to be involved in tumor progression. Because objective response of clinical patients to erbB-targeted therapies like CI-1033 has been observed only in a subset of cancer patients that exhibit the intended molecular targets, much emphasis has been placed on the identification of biomarkers of antitumor efficacy. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) were considered as potential biomarkers for CI-1033 due to ease of detection in patient plasma and showed roles in angiogenesis and cancer progression and positive regulation by the erbB receptor family. In the present studies, mice bearing established xenografts (A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, SF767 glioblastoma, and MDA-MB-468 mammary carcinoma) were treated with efficacious and subefficacious doses of CI-1033, and plasma levels and xenograft gene expression of VEGF and IL-8 were evaluated. Oral administration of CI-1033 to tumor-bearing mice at efficacious doses resulted in markedly decreased levels of VEGF and/or IL-8 plasma levels and tumor mRNA levels relative to vehicle-treated control mice in xenograft models that exhibited evaluable levels of these markers. In contrast, subefficacious doses of CI-1033 did not significantly affect VEGF or IL-8 levels in any of the xenograft models. These studies indicate that plasma VEGF and IL-8 may have use as biomarkers of antitumor efficacy for epidermal growth factor receptor/erbB-targeted therapies such as CI-1033 and suggest that further clinical study of these markers in cancer patients are warranted.
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PMID:Plasma vascular endothelial growth factor and interleukin-8 as biomarkers of antitumor efficacy of a prototypical erbB family tyrosine kinase inhibitor. 1595 51

The lactate dehydrogenase (LDH) assay was addressed for its sensitivity, disturbances by foaming, and cell number and size. Cells were from a U-251 MG grade IV human glioblastoma brain tumor cell line used in 100-microl well volumes. Cells were counted by microscopy and Coulter counting; assays were LDH or trypan blue. The results indicate increased 490 nm signals (level, variance) by using phenol red or by increasing fetal bovine serum from 5% to 10%. The data also indicate that defoaming results in reduced variances ranging from a factor of 2 at 1-3 units of absorption, up to a factor of 4-5 at <1 units of absorption. Coulter counting indicated a decrease in cell volume with increasing end-point cell density, attributed to general shrinking at increasing density. In comparisons, total LDH was considered relative to both cell total volume and cell numbers. The result suggests that total LDH should be regarded as reflecting cell total volume rather than cell numbers. In a comparative Cu exposure test, signals of both LDH and a sodium salt of 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) decreased with increasing Cu supply, while bromodeoxyuridine signals remained largely unaffected. The data show the differences in responses in cell viability and proliferation, but, above all, indicate that LDH should be expressed on a per cell volume basis rather than per cell, to avoid the problem that mere density effects contribute to signals on compound or metal toxicity.
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PMID:Optimization, application, and interpretation of lactate dehydrogenase measurements in microwell determination of cell number and toxicity. 1643 62


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