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)

In earlier work it has been shown that mitochondrially bound brain hexokinase is solubilized by anesthetics. This effect was reevaluated using cultured cells. For the present experiments Ehrlich ascites, Harding-Passey melanoma, C-1300-neuroblastoma and C-6-glioma cells were used. The great portion of hexokinase activity bound to the mitochondria of these cells was similar to that in rat brain. After incubation with thiopental the soluble hexokinase activity was increased in all cells studied. Using neuroblastoma and glioma cells the thiopental effect was demonstrated to be dose-dependent. Thus, cultured tumor cells seem to be useful for studying the relationship of the intracellular distribution of hexokinase activity, energy metabolism and the effect of anesthetics.
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PMID:Influence of thiopental on intracellular distribution of hexokinase activity in various tumor cells. 719 88

Hexokinase plays a key role in regulating cell energy metabolism. Hexokinase is mainly particulate, bound to the mitochondrial outer membrane in brain and tumour cells. We hypothesized that the intracellular pH (pH1) controls the intracellular distribution of hexokinase. Using the SNB-19 glioma cell line, pH1 variations were imposed by incubating cells in a high-K+ medium at different pH values containing specific ionophores (nigericin and valinomycin), without affecting cell viability. Subcellular fractions of cell homogenates were analysed for hexokinase activity. Imposed pH1 changes were verified microspectrofluorimetrically by using the pH1-sensitive probe SNARF-1-AM (seminaphtho-rhodafluor-1-acetoxymethyl ester). Imposition of an acidic pH1 for 30 min strongly decreased the particulate/total hexokinase ratio, from 63% in the control sample to 31%. Conversely, when a basic pH1, was imposed, the particulate/total hexokinase ratio increased to 80%. The glycolytic parameters, namely lactate/pyruvate ratio, glucose 6-phosphate and ATP levels, were measured concomitantly. Lactate/pyruvate ratio and ATP level were both markedly decreased by acidic pH1 and increased by basic pH1. Conversely, the glucose 6-phosphate level was increased by acidic pH1 and decreased by basic pH1. To demonstrate that the change of hexokinase distribution was not due to altered metabolite levels of glycolysis, a pH1 was imposed for a 5 min incubation time. Modification of the hexokinase distribution was similar to that noted after a 30 min incubation, whereas metabolite levels of glycolysis were not affected. These results provide evidence that the intracellular distribution of hexokinase is highly sensitive to variations of the pH1, and regulates hexokinase activity.
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PMID:Intracellular pH governs the subcellular distribution of hexokinase in a glioma cell line. 861 Nov 81

In order to establish whether growth of glioma cells is associated with glucose transport and metabolism, we investigated expression of the glucose transporter and hexokinase, as well as glucose transport and glucose phosphorylation in rat C6 glioma cells growing at different rates. Rat C6 glioma cells were subcloned to produce four different cell lines (CL1, CL2, CL3 and CL4) differing in growth, differentiation and morphology: CL1 cells were slow-growing with an astrocytic appearance whereas CL4 cells grew rapidly and were small and spindle-shaped. Immunocytochemical analysis using glial fibrillary acidic protein and galactocerebroside antibodies revealed that CL1 and CL4 cells differentiate to astrocytes and oligodendrocytes respectively. Both of these cell lines expressed GLUT1 mRNA predominantly, whereas little GLUT3 mRNA was evident by Northern-blot analysis. The GLUT1 mRNA level was much higher in CL4 than in CL1 cells, and the uptake of 2-deoxy-D-glucose and 3-O-methyl-D-glucose by CL4 cells was markedly higher than that by CL1 cells, indicating a correlation between the growth rate, glucose transporter (GLUT1) level and glucose-transport rate of C6 glioma cells. We then studied glucose metabolism by CL1 and CL4 cells by measuring their hexokinase activities and intracellular concentrations of glucose and ATP. The mitochondrial hexokinase activity of CL4 cells was about three times higher than that of CL1 cells, whereas the cytosolic hexokinase activity of CL4 cells was only about half that of CL1 cells. As the total amount of cellular hexokinase protein in CL4 cells was only slightly higher (about 20%) than that in CL1 cells, the hexokinase protein of CL4 cells was considered to have moved from the cytosol to the mitochondrial membranes. Consistent with the increased mitochondrial hexokinase activity of CL4 cells, the intracellular glucose concentration was undetectable, and the ATP concentration was higher than that of CL1 cells, suggesting that glucose transport is the rate-limiting factor for overall glucose metabolism is rapidly growing C6 cells. Therefore the present data demonstrate that glioma cell growth is related to glucose transport, which is closely associated with glucose metabolism.
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PMID:Rat C6 glioma cell growth is related to glucose transport and metabolism. 891 84

To elucidate the reasons for glycolytic deviation commonly found in brain tumors, hexokinase (HK) activity, mitochondria-HK binding, oxidative phosphorylation and mitochondrial ultrastructure were studied in 4 human xenografted gliomas. Lactate/pyruvate ratios were increased 3-4 fold and HK activity was of 2-4 fold lower than that of normal rat brain tissue, used as the control. The mitochondria-bound HK (mHK) fraction varied considerably and represented 9 to 69% of the total HK of that normal rat brain. The respiratory activity of glioma mitochondria, assessed by polarography and spectrophotometry, was within the normal range. However, the mitochondrial content of gliomas was lower than in the rat brain tissue, as revealed by the markedly decreased, activities of two unrelated mitochondrial enzymes, cytochrome c oxidase and citrate synthase in glioma homogenates. Electron microscopical studies confirmed the reduced number of mitochondria in 3 out of the 4 gliomas. Profound alterations of mitochondrial ultrastructure, namely of cristae and matrix densities, were observed in the 4 gliomas. The intercrista space was wider in all gliomas and the crista area was larger in 3 out of the 4 gliomas than in normal rat brain. Finally, the outer membrane of glioma mitochondria interacted intimately and extensively with the rough endoplasmic reticulum (RER) and/or nuclear membrane. These results suggest that, because of the very low content of normally functioning mitochondria, gliomas shift their energy metabolism towards a high-level glycolysis to generate their cellular ATP supply, probably through RER-mitochondria interactions and transformation-dependent redistribution of particulate HK from non-mitochondrial to mitochondrial receptors.
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PMID:Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure. 921 43

Glucose-dependent energy required for glioma metabolism depends on hexokinase, which is mainly bound to mitochondria. A decrease in intracellular pH leads to a release of hexokinase-binding, which in turn decreases glucose phosphorylation, ATP content, and cell proliferation. Thus, intracellular pH might be a target for therapy of gliomas, and a search for agents able to modulate intracellular pH was initiated. Hypericin, a natural photosensitizer, displays numerous biological activities when exposed to light. Its mechanism and site of action at the cellular level remain unclear, but it probably acts by a type II oxygen-dependent photosensitization mechanism producing singlet oxygen. Hypericin is also able to induce a photogenerated intracellular pH drop, which could constitute an alternative mechanism of hypericin action. In human glioma cells treated for 1 h with 2.5 microg/ml hypericin, light exposure induced a fall in intracellular pH. In these conditions, mitochondria-bound hexokinase was inhibited in a light- and dose-dependent manner, associated with a decreased ATP content, a decrease of mitochondrial transmembrane potential, and a depletion of intracellular glutathione. Hexokinase protein was effectively released from mitochondria, as measured by an ELISA using a specific anti-hexokinase antibody. In addition to decreased glutathione, a response to oxidative stress was confirmed by the concomitant increase in mRNA expression of gamma-glutamyl cysteine synthetase, which catalyzes the rate-limiting step in overall glutathione biosynthesis, and is subject to feedback regulation by glutathione. Hypericin also induced a dose- and light-dependent inhibition of [3H]thymidine uptake and induced apoptosis, as demonstrated by annexin V-FITC binding and cell morphology. This study confirmed the mitochondria as a primary target of photodynamic action. The multifaceted action of hypericin involves the alteration of mitochondria-bound hexokinase, initiating a cascade of events that converge to alter the energy metabolism of glioma cells and their survival. In view of the complex mechanism of action of hypericin, further exploration is warranted in a perspective of its clinical application as a potential phototoxic agent in the treatment of glioma tumors.
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PMID:Light-induced photoactivation of hypericin affects the energy metabolism of human glioma cells by inhibiting hexokinase bound to mitochondria. 986 36

Quantitative imaging of glucose metabolism of human brain tumors with PET utilizes 2-[(18)F]-fluorodeoxy-D-glucose (FDG) and a conversion factor called the lumped constant (LC), which relates the metabolic rate of FDG to glucose. Since tumors have greater uptake of FDG than would be predicted by the metabolism of native glucose, the characteristic of tumors that governs the uptake of FDG must be part of the LC. The LC is chiefly determined by the phosphorylation ratio (PR), which is comprised of the kinetic parameters (Km and Vmax) of hexokinase (HK) for glucose as well as for FDG (LC proportional to (Km(glc) x Vmax(FDG))/(Km(FDG) x Vmax(glc)). The value of the LC has been estimated from imaging studies, but not validated in vitro from HK kinetic parameters. In this study we measured the kinetic constants of bovine and 36B-10 rat glioma HK I (predominant in normal brain) and 36B-10 glioma HK II (increased in brain tumors) for the hexose substrates glucose, 2-deoxy-D-glucose (2DG) and FDG. Our principal results show that the KmGlc < KmFDG << Km2DG and that PR2DG < PRFDG. The FDG LC calculated from our kinetic parameters for normal brain, possessing predominantly HK I, would be higher than the normal brain LC predicted from animal studies using 2DG or human PET studies using FDG or 2DG. These results also suggest that a shift from HK I to HK II, which has been observed to increase in brain tumors, would have little effect on the value of the tumor LC.
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PMID:Kinetic characterization of hexokinase isoenzymes from glioma cells: implications for FDG imaging of human brain tumors. 1129 20

An easy and fast method for the quantitative analysis of nucleotides by capillary zone electrophoresis was developed. The method employing a neutral-bonded capillary and reversed polarity mode provided a good resolution and a short analysis time of less than 5 min. The samples were injected electrokinetically using -6 kV voltage for 30 s and detected by their UV absorbance at 254 nm. Constant current (-45 microA) was applied, and a phosphate buffer, pH 7.4, was used. The detection limits for ATP, UDP, and UTP ranged between 0.14 and 0.28 microM. This method was required for the investigation of the purity of the commercially available nucleotides used in pharmacological studies. In addition, the analytical method was applied to study the metabolism of nucleotides in a cell line, neuroblastoma x glioma hybrid cells (NG108-15), which is used in pharmacological studies with nucleotides, since it contains purine- and pyrimidine-sensitive nucleotide receptors. Furthermore, we used the new method for monitoring enzymatic studies using the enzyme hexokinase to convert nucleotide triphosphates to diphosphates.
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PMID:Fast, efficient capillary electrophoresis method for measuring nucleotide degradation and metabolism. 1206 39

Treatment with nerve growth factor (NGF) causes differentiation of rat C6 glioma cells and strongly inhibits their proliferation in vitro. This suggests that induction of NGF-mediated differentiation may provide a novel therapeutic approach to growth control of glial tumors. We examined the effects of NGF treatment on the growth potential of C6 glioma, which expressed NGF receptor in vivo. C6 glioma cells (1 x 10(6) cells/10 microl) were transplanted into the rat striatum. After 4 days, the animals were given successive injections of 100 ng NGF into the growing tumor at every 4 days (n = 10 rats). Controls were subjected to identical procedures with vehicle which did not contain NGF (n = 10 rats). At 14 days after transplantation, we evaluated the tumor volume, proliferative cell index (PCI) based on the MIB-1 immunoreactivity and enzyme activities related to energy metabolism by enzyme histochemistry. We found that the NGF treatment markedly reduced the tumor volume of the C6 glioma (34.00 +/- 8.47 mm3 to 7.22 +/- 4.92 mm3, p < 0.01). NGF treatment also decreased the PCI (33.34 +/- 9.57% to 3.85 +/- 3.56%, p < 0.01) with a negative correlation with tumor volume (r = 0.972, p < 0.01), and the hexokinase (HK) and glucose-6-phosphate dehydrogenase (G6PDH) activities (p < 0.01 and p < 0.01, respectively) which reflect the demand for nucleic acid synthesis for proliferation through the glycolytic and pentose phosphate pathways. The present results demonstrate for the first time that inhibition of tumor cell proliferation of C6 glioma by NGF occurs in vivo, probably through the NGF-mediated differentiation of C6 glioma cells which has been observed in in vitro studies.
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PMID:Growth control of C6 glioma in vivo by nerve growth factor. 1224 Nov 15

To prepare near-infrared fluorescence imaging and photodynamic therapy agents targeted at glucose transporters, pyropheophorbide 2-deoxyglucosamide (Pyro-2DG) was synthesized and evaluated in a 9L glioma rat model. Fluorescence imaging studies demonstrate that Pyro-2DG is selectively accumulated in the tumor. Upon its photoactivation, we demonstrate that this agent efficiently causes selective mitochondrial damage to the region of a tumor that was photoirradiated after administration of this agent, but does not affect tissues photoirradiated in the absence of the agent or tissues treated with the agent that are not photoirradiated. Preliminary confocal microscopy studies suggest that Pyro-2DG is delivered and trapped in tumor cells via the GLUT/hexokinase pathway and therefore is useful both as a tumor-targeted NIR fluorescence imaging probe and as a PDT agent for the destruction of cancer.
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PMID:Pyropheophorbide 2-deoxyglucosamide: a new photosensitizer targeting glucose transporters. 1286 22

Gliomas are the most common types of brain tumors. Although sophisticated regimens of conventional therapies are being carried out to treat patients with gliomas, the disease invariably leads to death over months or years. Before new and potentially more effective treatment strategies, such as gene- and cell-based therapies, can be effectively implemented in the clinical application, certain prerequisites have to be established. First of all, the exact localization, extent, and metabolic activity of the glioma must be determined to identify the biologically active target tissue for a biological treatment regimen; this is usually performed by imaging the expression of up-regulated endogenous genes coding for glucose or amino acid transporters and cellular hexokinase and thymidine kinase genes, respectively. Second, neuronal function and functional changes within the surrounding brain tissue have to be assessed in order to save this tissue from therapy-induced damage. Third, pathognomonic genetic changes leading to disease have to be explored on the molecular level to serve as specific targets for patient-tailored therapies. Last, a concerted noninvasive analysis of both endogenous and exogenous gene expression in animal models as well as the clinical setting is desirable to effectively translate new treatment strategies from experimental into clinical application. All of these issues can be addressed by multi-modal radionuclide and magnetic resonance imaging techniques and fall into the exciting and fast growing field of molecular and functional imaging. Noninvasive imaging of endogenous gene expression by means of positron emission tomography (PET) may reveal insight into the molecular basis of pathogenesis and metabolic activity of the glioma and the extent of treatment response. When exogenous genes are introduced to serve for a therapeutic function, PET imaging may reveal the assessment of the "location," "magnitude," and "duration" of therapeutic gene expression and its relation to the therapeutic effect. Detailed reviews on molecular imaging have been published from the perspective of radionuclide imaging (Gambhir et al., 2000; Blasberg and Tjuvajev, 2002) as well as magnetic resonance and optical imaging (Weissleder, 2002). The present review focuses on molecular imaging of gliomas with special reference on the status and perspectives of imaging of endogenous and exogenously introduced gene expression in order to develop improved diagnostics and more effective treatment strategies of gliomas and, in that, to eventually improve the grim prognosis of this devastating disease.
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PMID:Molecular imaging of gliomas. 1292 28


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