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)

Inducible nitric oxide synthase (iNOS or NOS2) is expressed in malignant glioma. Previously we noted that C6 glioma cells overexpressing NOS2 displayed chemoresistance against 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and other chloroethylnitrosourea derivatives with carbamoylating action. Herein we report experimental evidence supporting the contention that this NOS2 effect is mediated, at least in part, by S-nitrosoglutathione (GSNO), a potent antioxidant derived from interaction of NO and glutathione. Out of three NO donors tested, only GSNO was effective in protecting glioma cells against BCNU cytotoxicity. Furthermore, the protective effect of GSNO, similar to that of NOS2, was confined to carbamoylating, but not alkylating action. Experimental manipulations that were expected to increase or decrease cellular GSNO stores, as confirmed by immunocytochemical staining using a GSNO-specific antibody and HPLC analysis of GSNO contents in culture medium, led respectively to enhanced or reduced chemoresistance against carbamoylating cytotoxicity. Finally, neocuproine, a selective cuprous ion chelator known to neutralize GSNO actions, abolished NOS2-mediated chemoresistance against carbamoylating agents. Our results reveal a novel action of NOS2/GSNO that may potentially contribute to the development of chemoresistance against BCNU, which remains a mainstay in chemotherapy for glioblastoma multiforme.
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PMID:Nitric oxide and BCNU chemoresistance in C6 glioma cells: role of S-nitrosoglutathione. 1511 Mar 96

Malignant gliomas, most of which show an elevated level of vascular endothelial cell growth factor (VEGF) expression, are well known for their hyper-vascularity. One of the possible inducers of VEGF in tumor cells is nitric oxide (NO), which is synthesized by NO synthase and stimulates soluble guanylate cyclase (GC) in tumor cells. Here, we report that 2 of 9 human glioma cell lines, CCF-STTG1 and U-87MG, overproduced cyclic GMP (cGMP) and showed increased expression of both or either subunits of soluble GC1, GUCY1A3 and GUCY1B3. Transfection of antisense GUCY1A3 or GUCY1B3 into these two glioma cell lines markedly reduced the content of cGMP and expression of VEGF. The angiogenic activity in vitro was subsequently inhibited, which was determined by induction of HUVEC cell growth. Furthermore, subcutaneous tumor formation by U-87MG cells in nude mice was dramatically suppressed to less than 0.05% in volume by transfection of either antisense GUCY1A3 or antisense GUCY1B3, which was accompanied by the significant decrease in vascular index to about 10%. These findings demonstrate that cGMP is an upstream mediator of VEGF expression in glioma cells and that soluble guanylate cyclases could be the target molecules for controlling neo-vascularization in a subset of human malignant gliomas.
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PMID:Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3. 1520 57

The present study was designed to clarify the involvement of nitric oxide (NO) signaling in the adverse effect of cyclosporine on the blood-brain barrier. Cyclosporine increased the permeability of sodium-fluorescein and the cellular accumulation of rhodamine 123, a substrate of P-glycoprotein, in mouse brain endothelial (MBEC4) cells. This effect was markedly enhanced two- to threefold when MBEC4 cells were cocultured with rat astrocytes or C6 glioma cells. Direct and continuous electrochemical measurement of NO demonstrated that cyclosporine dose-dependently increased histamine- and phenylephrine-evoked NO production in MBEC4 cells and astrocytes, respectively. A NO synthase inhibitor (NG-monomethyl-L-arginine) blocked slightly and markedly cyclosporine-induced impairment of the endothelial barrier in the monolayer and coculture system, respectively. These findings suggest that cyclosporine impairs the brain endothelial barrier function by accelerating NO production in the brain endothelial and astroglial cells. This event may be interpreted as triggering the occurrence of cyclosporine neurotoxicity.
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PMID:Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in cocultures of mouse brain endothelial cells and rat astrocytes. 1555 36

The influence of environmental pH on the production of tumoricidal free radical nitric oxide (NO) was investigated in mouse fibrosarcoma L929 and rat glioma C6 cell lines. A combination of IFN-gamma and IL-1 induced a significant NO release and subsequent reduction of cell viability in tumor cell lines. Acidification of cell culture medium reduced tumor cell NO production in a pH-dependent manner. While the inhibitory effect of acidosis on NO production in C6 cells was associated with a further decrease in cell viability, it completely rescued L929 cells from NO-dependent apoptotic and necrotic death. Acidic pH diminished IFN-gamma+ IL-1-induced expression of inducible NO synthase (iNOS) mRNA and protein, and abolished the activation of iNOS transcription factor IRF-1 in L929 cells. Moreover, extracellular acidosis significantly impaired cytokine-induced phosphorylation of MAP kinase p44/42 (ERK1/2) and subsequent expression of transcription factor c-Fos in L929 cells. Finally, mild acidosis (pH 6.8) augmented, while severe acidosis (pH 6.0) reduced, IFN-gamma-induced iNOS activation/NO release and NO-dependent anticancer activity of rat and mouse macrophages. Taken together, our findings indicate that modulation of macrophage and tumor cell iNOS by an acidic microenvironment might influence the progression of NO-sensitive solid tumors.
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PMID:Acidosis affects tumor cell survival through modulation of nitric oxide release. 1641 2

Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV), and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) in tissues and biological fluids is the biochemical hallmark of patients affected by the neurometabolic disorder known as maple syrup urine disease (MSUD). Considering that brain energy metabolism is possibly altered in MSUD, the objective of this study was to determine creatine kinase (CK) activity, a key enzyme of energy homeostasis, in C6 glioma cells exposed to BCKA. The cells were incubated with 1, 5, or 10 mM BCKA for 3 h and the CK activity measured afterwards. The results indicated that the BCKA significantly inhibited CK activity at all tested concentrations. Furthermore, the inhibition caused by the BCKA on CK activity was totally prevented by preincubation with the energetic substrate creatine and by coincubation with the N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, indicating that deficit of energy and nitric oxide (NO) are involved in these effects. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble Vitamin E) were not able to prevent CK inhibition. In addition, we observed that the C6 cells changed their usual rounded morphology when exposed for 3 h to 10 mM BCKA and that creatine and L-NAME prevented these morphological alterations. Considering the importance of CK for brain metabolism homeostasis, it is conceivable that inhibition of this enzyme by increased levels of BCKA may contribute to the neurodegeneration of MSUD patients.
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PMID:Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. 1663 2

This study examines the influence of insoluble matrix components of glioma (astrocytoma) cells on LPS-mediated inducible nitric oxide (NO)/NO synthase (iNOS) induction in microglia cells. Insoluble matrix components prepared from C6 rat glioma cells strongly suppressed iNOS induction and subsequent NO release induced by LPS. Matrices prepared from several glioma cell lines displayed similar inhibitory effects on LPS-induced NO/iNOS induction, whereas matrices from primary cultured rat astrocytes had a minimal influence. Of the various purified ECM materials examined, collagen suppressed LPS-mediated iNOS/NO induction in microglia. C6 matrices potentiated LPS-induced NF-kappaB DNA binding/transcriptional activity, suggesting that the suppression of LPS-induced iNOS by C6 matrices is NF-kappaB independent. C6 matrices inhibited LPS-mediated activation of p38 and JNK MAP kinases. This study shows that non-diffusible factors derived from astrocytoma cells in the brain are critically involved in the suppression of microglial cell activation. Our results indicate that activation of microglia can be regulated by various cellular and pathological environmental conditions, not only through cell-cell contact or soluble factors, but also via insoluble matrix components.
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PMID:Insoluble matrix components of glioma cells suppress LPS-mediated iNOS/NO induction in microglia. 1684 40

Bystander responses have been reported to be a major determinant of the response of cells to radiation exposure at low doses, including those of relevance to therapy. This study investigated the role of changes in calcium levels in bystander responses leading to chromosomal damage in nonirradiated T98G glioma cells and AG01522 fibroblasts that had been either exposed to conditioned medium from irradiated cells or co-cultured with a population where a fraction of cells were individually targeted through the nucleus or cytoplasm with a precise number of microbeam helium-3 particles. After the recipient cells were treated with conditioned medium from T98G or AG01522 cells that had been irradiated through either nucleus or cytoplasm, rapid calcium fluxes were monitored in the nonirradiated recipient cells. Their characteristics were dependent on the source of the conditioned medium but had no dependence on radiation dose. When recipient cells were co-cultured with an irradiated population of either T98G or AG01522 cells, micronuclei were induced in the nonirradiated cells, but this response was eliminated by treating the cells with calcicludine (CaC), a potent blocker of Ca(2+) channels. Moreover, both the calcium fluxes and the bystander effect were inhibited when the irradiated T98G cells were treated with aminoguanidine, an inhibitor of nitric oxide synthase (NOS), and when the irradiated AG01522 cells were treated with DMSO, a scavenger of reactive oxygen species (ROS), which indicates that NO and ROS were involved in the bystander responses generated from irradiated T98G and AG01522 cells, respectively. Our findings indicate that calcium signaling may be an early response in radiation-induced bystander effects leading to chromosome damage.
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PMID:Calcium fluxes modulate the radiation-induced bystander responses in targeted glioma and fibroblast cells. 1695 66

Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV) and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) occurs in tissues and biological fluids of patients affected by the neurometabolic disorder maple syrup urine disease (MSUD). The objective of this study was to verify the effect of the BCKA on S100B release from C6 glioma cells. The cells were exposed to 1, 5 or 10 mM BCKA for different periods and the S100B release was measured afterwards. The results indicated that KIC and KIV, but not KMV, significantly enhanced S100B liberation after 6 h of exposure. Furthermore, the stimulatory effect of the BCKA on S100B release was prevented by coincubation with the energetic substrate creatine and with the N-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, indicating that energy deficit and nitric oxide (NO) were probably involved in this effect. Furthermore, the increase of S100B release was prevented by preincubation with the protein kinase inhibitors KN-93 and H-89, indicating that KIC and KIV altered Ca2+/calmodulin (PKCaMII)- and cAMP (PKA)-dependent protein kinases activities, respectively. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble vitamin E) were not able to prevent KIC- and KIV-induced increase of S100B liberation, suggesting that the alteration of S100B release caused by the BCKA is not mediated by oxidation of sulfydryl or other essential groups of the enzyme as well as by lipid peroxyl radicals. Considering the importance of S100B for brain regulation, it is conceivable that enhanced liberation of this protein by increased levels of BCKA may contribute to the neurodegeneration characteristic of MSUD patients.
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PMID:Effect of the branched-chain alpha-keto acids accumulating in maple syrup urine disease on S100B release from glial cells. 1749 67

The glitazones (or thiazolidinediones) are synthetic compounds used in type-2 diabetes, but they also have broad antiproliferative and anti-inflammatory properties still not well understood. We described previously the apoptotic effects of glitazones on astroglioma cells ( J Biol Chem 279: 8976-8985, 2004 ). At certain concentrations, we found a selective lethality on glioma cells versus astrocytes that was dependent on a rapid production of reactive oxygen species (ROS) and seemed unrelated to the receptor peroxisome proliferator activated receptor-gamma. The present study was aimed at characterizing the oxygen derivatives induced by ciglitazone, rosiglitazone, and pioglitazone in C6 glioma cells and to investigate their intracellular source. We examined the interaction of ROS with nitric oxide (NO) and its consequences for glioma cell survival. Fluorescence microscopy and flow cytometry showed that glitazones induced superoxide anion, peroxynitrite, and hydrogen peroxide, with ciglitazone being the most active. ROS production was completely prevented by uncoupling of the electron transport chain and by removal of glucose as an energy substrate, whereas it was unaffected by inhibition of NADPH-oxidase and xanthine-oxidase. Moreover, glitazones inhibited state 3 respiration in permeabilized cells, and experiments with mitochondrial inhibitors suggested that complex I was the likely target of glitazones. Therefore, these results point to the mitochondrial electron transport chain as the source of glitazone-induced ROS in C6 cells. Glitazones also depolarized mitochondria and reduced mitochondrial pH. NO synthase inhibitors revealed that superoxide anion combines with NO to yield peroxynitrite and that the latter contributes to the cytotoxicity of glitazones in astroglioma cells. Future antitumoral strategies may take advantage of these findings.
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PMID:Glitazones induce astroglioma cell death by releasing reactive oxygen species from mitochondria: modulation of cytotoxicity by nitric oxide. 1750 46

High-grade gliomas are one of the most aggressive human tumors with <1% of patients surviving 5 years after surgery. Immunotherapy could offer a possibility to eradicate remnant tumor cells after conventional therapy. Experimental immunotherapy can induce partial cure of established intracerebral tumors in several rodent models. One reason for the limited therapeutic effects could be immunosuppression induced by both the growing tumor and the induced immune reaction. NO has been implicated in tumor-derived immune suppression in tumor-bearing hosts, and unspecific inhibitors of NO synthase have been shown to boost antitumor immunity. In this study, we show that the inducible NO synthase (iNOS)-specific inhibitor mercaptoethylguanidine (MEG) superiorly enhanced lymphocyte reactivity after polyclonal stimulation compared with the iNOS-specific inhibitor L-NIL and the unspecific NO synthase inhibitor L-NAME. Both iNOS inhibitors increased the number and proliferation of T cells but not of B cells. When combined during postimmunization with IFN-gamma-secreting N32 rat glioma cells of rats harboring intracerebral tumors, only MEG increased the cure rate. However, this was only achieved when MEG was administered after immunizations. These findings implicate that NO has both enhancing and suppressive effects after active immunotherapy.
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PMID:Postimmunization with IFN-gamma-secreting glioma cells combined with the inducible nitric oxide synthase inhibitor mercaptoethylguanidine prolongs survival of rats with intracerebral tumors. 1778 63


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