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)

The glitazones or thiazolidinediones are ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma). The glitazones are used in the treatment of diabetes, regulate adipogenesis, inflammation, cell proliferation, and induce apoptosis in several cancer cell types. High grade astrocytomas are rapidly growing tumors derived from astrocytes, for which new treatments are needed. We determined the effects of two glitazones, ciglitazone and the therapeutic rosiglitazone, on the survival of serum-deprived primary rat astrocytes and glioma cell lines C6 and U251, which were assessed by the methylthiazolyl tetrazolium assay and lactate dehydrogenase release. Rosiglitazone (5-20 microM) decreased survival of glioma cells without affecting primary astrocytes, whereas ciglitazone at 20 microM was toxic for both cell types. Ciglitazone at 10 microM was cytoprotective for primary astrocytes but toxic to glioma cells. Cell death induced by ciglitazone, but not rosiglitazone, presented apoptotic features (Hoechst staining and externalization of phosphatidylserine). Two mechanisms to explain cytotoxicity were investigated: activation of PPARgamma and production of reactive oxygen species (ROS). PPARgamma does not seem to be the main mechanism involved, because the order of efficacy for cytotoxicity, ciglitazone > rosiglitazone, was inverse of their reported affinities for activating PPARgamma. In addition, GW9662, an inhibitor of PPARgamma, only slightly attenuated cytotoxicity. However, the rapid increase in ROS production and the marked reduction of cell death with the antioxidants ebselen and N-acetylcysteine, indicate that ROS have a key role in glitazone cytotoxicity. Ciglitazone caused a dose-dependent and rapid loss (in minutes) of mitochondrial membrane potential in glioma cells. Therefore, mitochondria are a likely source of ROS and early targets of glitazone cytotoxicity. Our results highlight the potential of rosiglitazone and related compounds for the treatment of astrogliomas.
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PMID:Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma. 1469 30

Intracerebral C6 glioma xenografts spontaneously develop centrally located necrotic regions that are bordered by densely packed neoplastic cells. Proliferative and metabolic heterogeneity in these perinecrotic regions were assessed by bromodeoxyuridine (BrdU) incorporation, by immunocytological and by histochemical analyses. The borders of necrotic regions are comprised of glioma cells that express increased levels of the type 1 glucose transporter (GLUT-1) with rare cells having incorporated BrdU. By contrast, BrdU-positive glioma cells are located immediately adjacent to GLUT-1-positive cells bordering areas of necrosis. BrdU-positive glioma cells are also scattered throughout poorly vascularized, central regions of the tumor and are present at the highly vascularized tumor periphery. GLUT-1 expression increased considerably when C6 glioma cells were grown for 48 h under either the acidotic conditions of pH 6.8 or under hypoxic conditions. The perinecrotic GLUT-1-positive glioma cells in poorly vascularized, centrally located tumor regions demonstrated a 75% reduction in glycogen content and negligible glycogenolytic capacity, when compared with normal brain white matter. Cytochrome c oxidase (COX) and lactate dehydrogenase (LDH) maintained 50% enzymatic activity compared to controls, while succinate dehydrogenase (SDH) activity was 25% of control values. Based upon these findings, a metabolic model is proposed in which GLUT-1-positive perinecrotic cells are growth arrested and predominantly rely upon non-oxidative glycolysis. It is further postulated that BrdU-positive, GLUT-1-negative glioma cells within the poorly vascularized, central tumor region convert glucose-6-phosphate to nucleotide precursors for DNA replication.
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PMID:Perinecrotic glioma proliferation and metabolic profile within an intracerebral tumor xenograft. 1471

Brain tumors are frequently treated with steroids due to the presence of peritumoral edema. However, in Japan it is not widely recognized that primary brain tumor patients who are receiving steroid therapy become susceptible to Pneumocystis carinii pneumonia (PCP). We reviewed the clinical features and risk factors for PCP in brain tumor patients treated at our institution between 1994 and 2002. The treated cases consisted of 6 men and 6 women ranging in age from 47 to 78 yr (mean age 65.3). Underlying diseases included malignant glioma in 9 patients, malignant lymphoma in 2 patients and meningioma in one patient. All were diagnosed by respiratory disease specialists using bronchial washings and bronchoalveolar lavage or chest X ray/CT image. Radiation therapies were administered with 20 to 60 Gy (mean 52.9 Gy) except in one patient. Chemotherapy was performed with ranimustine in 4 malignant glioma patients and with methotrexate in 2 malignant lymphoma patients. Prednisone, begun perioperatively, was reduced gradually from a mean initial dosage of 38.3 mg/day orally. The duration of steroid treatment at the onset of PCP in these patients ranged from 41 to 79 days (mean 61.4 days). Six patients (50%) died of PCP despite appropriate antibiotic therapy and 2 patients needed intensive therapy with a respirator. For early diagnosis of PCP, periodic serological (e.g.; the level of lactate dehydrogenase and beta-D-glucan) and radiological examination (e.g.; chest X ray and CT image) is indicated in patients with brain tumors, and prophylaxis against PCP might be needed for patients with intracranial neoplasms and who are also receiving high-dose and long-term steroid treatment.
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PMID:[Pneumocystis carinii pneumonia complicating brain tumor]. 1503 73

Degradation of adenine nucleotides in myocardial cells has important physiological implications associated with the regulation of the high-energy phosphate precursor pool and the production of adenosine. Adenosine may be released as from cells or, following adenine nucleotides release, they may be metabolized and rapidly converted to adenosine via the action of an ectoenzyme cascade formed by an ATP diphosphohydrolase and a 5'-nucleotidase. Thyroid hormones are known to have profound effects on the cardiovascular system, as demonstrated by the changes accompanying both hypothyroidism and hyperthyroidism. We previously reported that thyroid hormone significantly increases the ecto-5'-nucleotidase (CD73) activity and expression in C6 glioma cells culture. The object of the present study was to evaluate the extracellular adenosine production from AMP in cardiomyocytes and also the effect of (T3) on activity and expression of the enzyme, CD73. Primary cultures of rat ventricular neonatal cardiac myocytes were submitted to increasing doses of T3 for 24 h. Cell viability and purity were estimated by measuring the release of lactate dehydrogenase (LDH) activity and immunofluorescence cell staining, respectively. CD73 activity was measurement using a malachite green method and RT-PCR was used to analyze enzyme expression. T3 stimulated CD73 activity and expression of the cells, suggesting that this effect could promote an increase in adenosine formation and, therefore, has an important modulatory role in the elicitation of responses that serve to restore the tissue oxygen supply-to-demand ratio back to normal.
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PMID:Thyroid hormone stimulates 5'-ecto-nucleotidase of neonatal rat ventricular myocytes. 1554 49

We report a novel ((13)C, (2)H) nuclear magnetic resonance (NMR) procedure to investigate lactate recycling through the monocarboxylate transporter of the plasma membrane of cells in culture. C6 glioma cells were incubated with [3-(13)C]lactate in Krebs-Henseleit Buffer containing 50% (2)H(2)O (vol/vol) for up to 30 hr. (13)C NMR analysis of aliquots progressively taken from the medium, showed: (1) a linearly decreasing singlet at approximately 20.85 parts per million (ppm; -0.119 micromol/mg protein/hr) derived from the methyl carbon of [3-(13)C]lactate; and (2) an exponentially increasing shifted singlet at approximately 20.74 ppm (0.227 micromol/ mg protein/hr) from the methyl carbon of [3-(13)C, 2-(2)H]lactate. The shifted singlet appears because during its transit through the cytosol, [3-(13)C]lactate generates [3-(13)C, 2-(2)H]lactate in the lactate dehydrogenase (LDH) equilibrium, which may return to the incubation medium through the reversible monocarboxylate carrier. The methyl group of [3-(13)C, 2-(2)H]lactate is shifted -0.11 ppm with respect to that of [3-(13)C]lactate, making it possible to distinguish between both molecules by (13)C NMR. During incubations with 2.5 mM [1-(13)C]glucose and 3.98 mM [U-(13)C(3)]lactate or with 2.5 mM [1-(13)C]glucose and 3.93 mM [2-(13)C]pyruvate, C2-deuterated lactate was produced only from [1-(13)C]glucose or [U-(13)C(3)]lactate, revealing that this deuteration process is redox sensitive. When [1-(13)C]glucose and [U-(13)C(3)]lactate were used as substrates, no significant [3-(13)C]lactate production from [1-(13)C]glucose was detected, suggesting that glycolytic lactate production may be stopped under the high lactate concentrations prevailing under mild hypoxic or ischemic episodes or during cerebral activation.
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PMID:Futile cycling of lactate through the plasma membrane of C6 glioma cells as detected by (13C, 2H) NMR. 1556 38

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Resveratrol has antiinflammatory and antioxidant properties, and also has potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an anticancer agent, since glioma is a particularly difficult cancer to treat and eradicate. Our data show that resveratrol induces dose- and time-dependent death of U251 cells, as measured by lactate dehydrogenase release and internucleosomal DNA fragmentation assays. Resveratrol induces activation of caspase-3 and increases the cleavage of the downstream caspase substrate, poly(ADP-ribose) polymerase. Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor (Z-VAD-FMK) or a selective caspase-3 inhibitor (Z-DEVD-FMK), but not by a selective caspase-1 inhibitor. Resveratrol induces cytochrome c release from mitochondria to the cytoplasm and activation of caspase-9. Resveratrol also increases expression of proapoptotic Bax and its translocation to the mitochondria. Resveratrol inhibits U251 proliferation, as measured by MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and induces G0/G1 growth arrest, as determined by flow cytometry. The cyclin-dependent kinase inhibitor, olomoucine, prevents cell cycle progression and resveratrol-induced apoptosis. These results suggest that multiple signaling pathways may underlie the apoptotic death of U251 glioma induced by resveratrol, which warrants further exploration as an anticancer agent in human glioma.
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PMID:Resveratrol-induced apoptotic death in human U251 glioma cells. 1582 28

The present study describes the ability of an anthraquinone derivative aloe emodin (AE) to reduce the cytotoxic activity of the platinum(II)-based anticancer agent cisplatin toward murine L929 fibrosarcoma and C6 glioma cell lines. The protective effect of AE was demonstrated by MTT and crystal violet assays for cell viability, and involved supression of cisplatin-induced apoptosis and necrosis, as assessed by lactate dehydrogenase release and flow cytometric analysis of DNA fragmentation or phosphatidylserine exposure. Cell-based ELISA and Western blot analysis revealed that AE abolished cisplatin-triggered activation of extracellular signal-regulated kinase (ERK) in tumor cells, while activation of c-Jun N-terminal kinase was not significantly altered. A selective blockade of ERK activation with PD98059 mimicked the protective effect of AE treatment in both tumor cell lines. Moreover, AE failed to protect tumor cells against the ERK-independent toxicity of the Pt(IV)-based complex tetrachloro(O,O-dibutyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV). Taken together, these data indicate that herbal anthraquinone AE can downregulate the anticancer activity of cisplatin by blocking the activation of ERK in tumor cells.
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PMID:Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin. 1590 60

A method for determination of lactate dehydrogenase (LDH) isoenzymes in single rat glioma cells (C6) was developed. In this method, a whole cell was electrokinetically injected into the front end of the separation capillary. After that, the cell was lysed by ultrasonication and the isoenzymes in the cell were pre-separated at 20 kV for 5 min and then incubated for 2 min with the enzyme substrates nicotinamide adenine dinucleotide (NAD(+)) and lactate in the capillary electrophoresis running buffer. The electroactive product NADH generated by the isoenzymes through on-capillary enzyme-catalyzed reaction was detected at the outlet of capillary by using the end-capillary amperometric detection with a constant potential mode at a carbon fiber bundle microdisk electrode. Since the amplification of signal via the enzyme reaction, the concentration of nicotinamide adenine dinucleotide (NADH) is much higher than that of LDH. The external standardization was used to quantify isoenzymes in individual cells. Three LDH isoenzymes in single rat glioma cells (C6) were determined and quantified.
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PMID:Determination of lactate dehydrogenase isoenzymes in single rat glioma cells by capillary electrophoresis with electrochemical detection. 1637 21

Large-conductance voltage- and calcium-sensitive channels are known to be expressed in the plasmalemma of central neurons; however, recent data suggest that large-conductance voltage- and calcium-sensitive channels may also be present in mitochondrial membranes. To determine the subcellular localization and distribution of large-conductance voltage- and calcium-sensitive channels, rat brain fractions obtained by Ficoll-sucrose density gradient centrifugation were examined by Western blotting, immunocytochemistry and immuno-gold electron microscopy. Immunoblotting studies demonstrated the presence of a consistent signal for the alpha subunit of the large-conductance voltage- and calcium-sensitive channel in the mitochondrial fraction. Double-labeling immunofluorescence also demonstrated that large-conductance voltage- and calcium-sensitive channels are present in mitochondria and co-localize with mitochondrial-specific proteins such as the translocase of the inner membrane 23, adenine nucleotide translocator, cytochrome c oxidase or complex IV-subunit 1 and the inner mitochondrial membrane protein but do not co-localize with calnexin, an endoplasmic reticulum marker. Western blotting of discrete subcellular fractions demonstrated that cytochrome c oxidase or complex IV-subunit 1 was only expressed in the mitochondrial fraction whereas actin, acetylcholinesterase, cadherins, calnexin, 58 kDa Golgi protein, lactate dehydrogenase and microtubule-associated protein 1 were not, demonstrating the purity of the mitochondrial fraction. Electron microscopic examination of the mitochondrial pellet demonstrated gold particle labeling within mitochondria, indicative of the presence of large-conductance voltage- and calcium-sensitive channels in the inner mitochondrial membrane. These studies provide concrete morphological evidence for the existence of large-conductance voltage- and calcium-sensitive channels in mitochondria: our findings corroborate the recent electrophysiological evidence of mitochondrial large-conductance voltage- and calcium-sensitive channels in glioma and cardiac cells.
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PMID:The calcium-sensitive large-conductance potassium channel (BK/MAXI K) is present in the inner mitochondrial membrane of rat brain. 1656 53

Compounds blocking the uptake of the endogenous cannabinoid anandamide (AEA) have been used to explore the functions of the endogenous cannabinoid system in the CNS both in vivo and in vitro. In this study, the effects of four commonly used acyl-based uptake inhibitors [N-(4-hydroxyphenyl)arachidonylamide (AM404), N-(4-hydroxy-2-methylphenyl) arachidonoyl amide (VDM11), (5Z,8Z,11Z,14Z)-N-(3-furanylmethyl)-5,8,11,14-eicosatetraenamide (UCM707) and (9Z)-N-[1-((R)-4-hydroxybenzyl)-2-hydroxyethyl]-9-octadecen-amide (OMDM2)] and the related compound arvanil on C6 glioma cell viability were investigated. All five compounds reduced the ability of the cells to accumulate calcein, reduced the total nucleic acid content and increased the activity of lactate dehydrogenase recovered in the cell medium. AM404 (10 microm) and VDM11 (10 microm) acted rapidly, reducing cell viability after 3 h of exposure when cell densities of 5,000 per well were used. In contrast, UCM707 (30 microm), OMDM2 (10 microm) and the related compound arvanil (10 microm) produced a more slowly developing effect on cell viability, although robust effects were seen after 6-9 h of exposure. At higher cell densities, the toxicities of AM404 and UCM707 were reduced. Comparison of the compounds with arachidonic acid, arachidonic acid methyl ester, AEA, arachidonoyl glycine and oleic acid suggested that the toxicity of the arachidonoyl-based compounds was related primarily to the acyl side-chain rather than the head group. A variety of pre-treatments blocking possible metabolic pathways and receptor targets were tested, but the only consistent protective treatment against the effects of these compounds was the antioxidant N-acetyl-L-cysteine. It is concluded that AM404, VDM11, UCM707 and OMDM2 produce a rapid loss of C6 glioma cell viability over the same concentration range as is required for the inhibition of AEA uptake in vitro, albeit with a longer latency. Such effects should be kept in mind when acyl-derived compounds are used to probe the function of the endocannabinoid system in the CNS, particularly in chronic administration protocols.
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PMID:Acyl-based anandamide uptake inhibitors cause rapid toxicity to C6 glioma cells at pharmacologically relevant concentrations. 1689 63


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