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)

Elevated vascular endothelial growth factor (VEGF) levels are required for ocular and tumor angiogenesis in animal models. Ischemic hypoxia is strongly correlated with increased VEGF expression in these systems and is considered a physiologically relevant stimulus. Because ischemic hypoxia is often followed by reperfusion and reactive oxygen intermediate (ROI) generation, we examined the potential role of ROI in the control of VEGF gene expression. Human retinal pigment epithelial cells exposed to superoxide or hydrogen peroxide rapidly increased VEGF mRNA levels. Superoxide-associated mRNA increases were dose dependent, blocked by antioxidants, and associated with elevated VEGF protein levels in conditioned media. Increases in VEGF mRNA levels were also observed in cultured human melanoma and rat glioblastoma cells with superoxide or hydrogen peroxide. Cycloheximide prevented the ROI-associated increases in VEGF mRNA. Transcriptional inhibition with actinomycin D revealed an inducible increase in VEGF mRNA half-life, but nuclear run-on experiments showed no increase in VEGF transcriptional rate. Reoxygenation of human retinal pigment epithelial cells in vitro and ocular reperfusion in vivo increased retinal VEGF mRNA levels. Antioxidants prevented the reperfusion-associated VEGF mRNA increases in retina. We conclude that ROIs increase VEGF gene expression in vitro and during the reperfusion of ischemic retina in vivo. The ROI-associated increases are mediated largely through increases in VEGF mRNA stability.
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PMID:Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. 883 17

A panel of eight human pancreatic tumour cell lines displayed high intrinsic radioresistance, with mean inactivation doses between 2.4 and 6.5 Gy, similar to those reported for melanoma and glioblastoma. The radiosensitising potency of sodium nitroprusside, a bioreductive nitric oxide donor, was assessed in a model of metabolism-induced hypoxia in a cell micropellet. Sodium nitroprusside at 0.1 mM revealed a radiosensitising effect with an overall enhancement ratio of 1.9 compared with 2.5 for oxygen. Radiosensitising activity correlated with the enhancement of single-strand DNA breakage caused by radiation. In suspensions with cell densities of between 3% and 30% (v/v), the half-life of sodium nitroprusside decreased from 31 to 3.2 min, suggesting a value of around 1 min for micropellets. Despite this variation, the radiosensitising activity was similar in micropellets and in diluted cell suspensions. S-nitroso-L-glutathione was found to possess radiosensitising activity, consistent with a possible role of natural thiols in the storing of radiobiologically active nitric oxide adducts derived from sodium nitroprusside. As measured by a nitric oxide-specific microsensor, activation of sodium nitroprusside occurred by bioreduction, whereas S-nitroso-L-glutathione showed substantial spontaneous decomposition. Both agents appear to exert radiosensitising action through nitric oxide as its scavenging by carboxy phenyltetramethylimidazolineoxyl N-oxide (carboxy-PTI0) and oxyhaemoglobin resulted in attenuated radiosensitisation. Sodium nitroprusside was at least 10-fold more potent than etanidazole, a 2-nitroimidazole used as a reference. Our data suggest that sodium nitroprusside, a drug currently used for the treatment of hypertension, is a potential tumour radioresponse modifier.
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PMID:Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside. 895 86

Up-regulation of vascular endothelial growth factor (VEGF) expression is a major event leading to neovascularization in malignant gliomas. Hypoxia is believed to be the crucial environmental stimulus for this up-regulation. To critically assess this hypothesis, we asked whether the mechanisms defined previously for hypoxia-induced VEGF expression in vitro are similarly involved and sufficient for up-regulation of VEGF gene expression in vivo, using a lacZ reporter gene under the control of VEGF regulatory sequences in an experimental glioma model. Inclusion of the binding site for hypoxia-inducible factor 1 (HIF 1) in the 5' regulatory sequences used in the hybrid gene produced weak beta-galactosidase staining in a special tumor cell subtype, the so-called perinecrotic palisading (PNP) cells that flank necrotic regions within the tumor. Deletion of the HIF 1 binding site abolished reporter gene expression in the PNP cells, indicating that transcriptional activation of VEGF expression in gliomas is mediated by HIF 1. Inclusion of 3' untranslated sequences from the VEGF gene in the reporter constructs resulted in an increased beta-galactosidase staining in the PNP cells, suggesting that mRNA stabilization also contributes to VEGF up-regulation in glioblastoma cells growing as solid tumors. Combination of the 5' flanking region including the HIF 1 site along with 3' untranslated sequences produced increased levels of beta-galactosidase expression in PNP cells. EF 5 immunostaining for regions of low oxygen partial pressure covered the same PNP cells that were stained for beta-galactosidase. Collectively, the data provide experimental evidence that VEGF gene expression is activated in a distinct tumor cell subpopulation, the perinecrotic palisading cells of gliomas, by two distinct hypoxia-driven regulatory mechanisms.
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PMID:Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms. 928

Leukocyte infiltration and necrosis are two biological phenomena associated with the development of neovascularization during the malignant progression of human astrocytoma. Here, we demonstrate expression of interleukin (IL)-8, a cytokine with chemotactic and angiogenic properties, and of IL-8-binding receptors in astrocytoma. IL-8 expression is first observed in low grade astrocytoma in perivascular tumor areas expressing inflammatory cytokines. In glioblastoma, it further localizes to oxygen-deprived cells surrounding necrosis. Hypoxic/anoxic insults on glioblastoma cells in vitro using anaerobic chamber systems or within spheroids developing central necrosis induced an increase in IL-8 messenger RNA (mRNA) and protein expression. mRNA for IL-8-binding chemokine receptors CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC) were found in all astrocytoma grades by reverse transcription/PCR analysis. In situ hybridization and immunohistochemistry localized DARC expression on normal brain and tumor microvascular cells and CXCR1 and CXCR2 expression to infiltrating leukocytes. These results support a model where IL-8 expression is initiated early in astrocytoma development through induction by inflammatory stimuli and later in tumor progression increases due to reduced microenvironmental oxygen pressure. Augmented IL-8 would directly and/or indirectly promote angiogenesis by binding to DARC and by inducing leukocyte infiltration and activation by binding to CXCR1 and CXCR2.
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PMID:Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. 933 59

Mechanism of merocyanine 540 (MC540) mediated photosensitization in glioblastoma (U-87MG) and neuroblastoma (Neuro 2a) cells was investigated. Photoinduced lipid peroxidation was measured in the presence of mechanistic probes-deuterium oxide (D2O), sodium azide, superoxide dismutase (SOD), mannitol and sodium benzoate. In both the types of cells, the photoinduced lipid peroxidation was enhanced in D2O whereas it showed inhibition in the presence of sodium azide. SOD also inhibited the lipid peroxidation while sodium benzoate and mannitol had no effect. These results suggest that photosensitization of U-87MG and Neuro 2a cells by MC 540 involves both type I (free radical mediated) and type II (singlet oxygen mediated) mechanisms.
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PMID:Mechanism of photosensitization of glioblastoma and neuroblastoma cells by merocyanine 540: a lipid peroxidation study. 949 48

It has been shown that astrocytes (human glioblastoma U118 cell line) release reactive oxygen species (ROS), including superoxide O2.- and hydrogen peroxide H2O2 following the action of C5a complement component C5a (but not C3a). The effect of C5a (1 nM) is accompanied with hyperpolarization of the astrocyte plasma membrane. Component C3a (100 nM), which is not an inducer of ROS, caused a prolonged depolarization of astrocytes. However, both the agents induced a transient increase in intracellular Ca2+ concentration. The data obtained permit a conclusion that O2.- participates in the intracellular signal transduction, and is involved in the mechanism of hyperpolarization response of astrocytes to the effect of the inducer of ROS, complement component C5a.
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PMID:[Activation of astrocytes of by anaphylatoxins of the complement system]. 982 Dec 47

Oxygen deprivation is an important biological feature of tumor growth. We previously showed that in glioma, anoxia increases expression of IL-8, a chemokine and angiogenic factor. Here, we analysed for the first time the biochemical mechanisms inducing the IL-8 gene upon anoxia in glioma cells, and showed that they differ from those inducing the VEGF gene. Both genes are induced in biologically and genetically heterogenous glioblastoma cell lines (LN-229, LN-Z308, U87MG, T98G), whereas, in gliosarcoma cells (D247MG), only the VEGF gene is induced. The kinetics of IL-8 and VEGF mRNA inductions differ in these cells and reoxygenation experiments showed that the induction is due to the anoxic stress per se. Furthermore, in LN-229 and LN-Z308 cell lines actinomycin D, DRB and nuclear run-on experiments showed that anoxia stimulates increased transcription of both genes. Electromobility shift assays show increased protein binding to the AP-1 site on the IL-8 promoter following anoxia treatment. Finally, in situ hybridization on glioblastoma sections shows that the in vivo expression patterns of IL-8 and VEGF genes overlap, but are not identical. Since intratumoral augmentation of IL-8 and VEGF secretion, following microenvironmental decreases in oxygen pressure, may promote angiogenesis, further definition of these pathways is essential to appropriately target them for antitumoral therapy.
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PMID:Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. 1005 Aug 81

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

Angiogenesis, the sprouting of new capillaries from preexisting blood vessels, results from a disruption of the balance between stimulatory and inhibitory factors. Here, we show that anoxia reduces expression of thrombospondin-1 (TSP-1), a natural inhibitor of angiogenesis, in glioblastoma cells. This suggests that reduced oxygen tension can promote angiogenesis not only by stimulating the production of inducers, such as vascular endothelial growth factor, but also by reducing the production of inhibitors. This downregulation may significantly contribute to glioblastoma development, since we show that an increase in TSP-1 expression is sufficient to strongly suppress glioblastoma cell tumorigenicity in vivo.
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PMID:Thrombospondin-1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. 1081 71

Glioblastomas are highly vascular malignant brain tumors that often overexpress vascular endothelial growth factor (VEGF). They also frequently overexpress epidermal growth factor receptor (EGFR) and contain regions of hypoxia, both conditions that can induce VEGF. We examined VEGF regulation in U87 MG human glioblastoma cells and in U87/T691 cells, a clonal derivative that contains a truncated erbB2/Neu receptor that interferes with EGFR signaling through the formation of nonfunctional heterodimeric receptor complexes. U87/T691 cells contained approximately one-half as much VEGF mRNA as did U87 MG cells under normoxic conditions (21% oxygen). Pharmacological inhibition of EGFR, Ras, or PI(3) kinase, but not MAP kinase, led to a significant decrease in VEGF mRNA levels in U87 MG cells. VEGF promoter activity in transient transfections was decreased by either pharmacological or genetic inhibition of EGFR, Ras, or phosphatidylinositol 3'-kinase [PI(3) kinase]. However, inhibition of PI(3) kinase or EGFR did not completely abolish induction of VEGF mRNA by hypoxia (0.2% oxygen). Likewise, VEGF mRNA expression was induced 3-fold by hypoxia in EGFR-inhibited U87/T691 cells, comparable with the fold induction seen in parental U87 MG cells, although the absolute level of message under hypoxia was higher in U87 MG cells. In transient transfections, a luciferase reporter construct containing a 1.2-kb fragment of the VEGF promoter, lacking the known hypoxic-responsive element (HRE), showed up-regulation after EGF stimulation to the same degree as the full-length, 1.5-kb VEGF promoter construct retaining the HRE. Furthermore, activity of the HRE-deleted, 1.2-kb promoter luciferase reporter was down-regulated by PI(3) kinase inhibition. Therefore, in glioblastoma cells, transcriptional regulation of the VEGF promoter by EGFR appears to involve Ras/PI(3) kinase and to be distinct from signals induced by hypoxia.
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PMID:Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3'-kinase and distinct from that induced by hypoxia. 1105 86


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