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 current study aimed to understand the anti-apoptotic effect of overexpressed gap junction forming protein connexin (Cx) 43 in C6 glioma cells. C6 cells exposed to hydrogen peroxide (H2O2) or staurosporine demonstrated morphological and biochemical changes consistent with apoptosis, whereas C6 cells expressing Cx43 demonstrated relative resistance to H2O2, but not to staurosporine. This selective protection against H2O2 was due to inhibition of caspase-3 activation in Cx43 expressing cells. siRNA knockdown experiments in rat primary astrocytes confirmed the presence of endogenous Cx43-mediated anti-apoptotic effect. Cx43 interacts with the upstream apoptosis signal-regulating kinase 1 known to mediate H2O2-induced apoptosis providing a possible mechanism for protection. These findings provided new evidence for regulation of the mitogen activated protein kinase pathway and apoptosis by Cx43 implicating this protein in intracellular signaling beyond its role as a gap junction forming protein on the plasma membrane.
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PMID:Connexin 43 confers resistance to hydrogen peroxide-mediated apoptosis. 1776 Nov 41

Although its concentration is generally not known, glutathione peroxidase-1 (GPx-1) is a key enzyme in the removal of hydrogen peroxide (H2O2) in biological systems. Extrapolating from kinetic results obtained in vitro using dilute, homogenous buffered solutions, it is generally accepted that the rate of elimination of H2O2 in vivo by GPx is independent of glutathione concentration (GSH). To examine this doctrine, a mathematical analysis of a kinetic model for the removal of H2O2 by GPx was undertaken to determine how the reaction species (H2O2, GSH, and GPx-1) influence the rate of removal of H2O2. Using both the traditional kinetic rate law approximation (classical model) and the generalized kinetic expression, the results show that the rate of removal of H2O2 increases with initial GPx(r), as expected, but is a function of both GPx(r) and GSH when the initial GPx(r) is less than H2O2. This simulation is supported by the biological observations of Li et al. Using genetically altered human glioma cells in in vitro cell culture and in an in vivo tumour model, they inferred that the rate of removal of H2O2 was a direct function of GPx activity x GSH (effective GPx activity). The predicted cellular average GPx(r) and H2O2 for their study are approximately GPx(r) < or =1 microm and H2O2 approximately 5 microm based on available rate constants and an estimation of GSH. It was also found that results from the accepted kinetic rate law approximation significantly deviated from those obtained from the more generalized model in many cases that may be of physiological importance.
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PMID:The rate of cellular hydrogen peroxide removal shows dependency on GSH: mathematical insight into in vivo H2O2 and GPx concentrations. 1788 26

We present here a suicide therapy against malignant gliomas based on the transfer to tumor cells of a gene encoding a beta-glucosidase, linamarase (lis), which in the presence of the innocuous substrate linamarin (lin) produces cyanide, blocking the mitochondrial respiratory chain. Dog glioma cells carrying the lis gene are thus sensitive to lin (IC(50) of 250 microg/mL at 48 hours) and cell death is accompanied by mitochondrial fission and ATP depletion. The combination of lis/lin with an otherwise nontoxic level of glucose oxidase (GO) enhances the therapeutic potential (IC(50) of 50 microg/mL at 48 hours). GO produces hydrogen peroxide, inducing oxidative damage and increasing cellular stress. We show here the antitumoral effect of the lis/lin/GO therapy in a canine glioma cell line and in a xenograft glioma model in nude mice. The synergic combination causes mitochondrial membrane depolarization and phosphatidylserine externalization and accelerates death by 48 hours. The lethal process is caspase independent; poly(ADP-ribose) polymerase 1 is not implicated; and there is no apoptosis-inducing factor translocation to the nucleus. The combined system induces autophagic cell death that can be rescued by 3-methyladenine and is characterized by the presence of double-membrane vesicles and punctate LC-3 pattern.
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PMID:Glioma regression in vitro and in vivo by a suicide combined treatment. 1833 48

Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2(val19). Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.
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PMID:Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. 1869 84

D-amino acid oxidase (DAAO) can catalyze the dehydrogenation of D-amino acids, such as D-alanine, to the corresponding amino acids and is then reoxidized by molecular oxygen to yield hydrogen peroxide, a reactive oxygen species, which reacts with DNA, lipids and protein, inducing cell death. This study investigated whether rat glioma 9L cells infected with the recombinant retrovirus containing the DAAO cDNA fragment can be induced in order to undergo cytotoxic oxidative stress by D-alanine. The recombinant retroviral vector, plzrus-DAAO-FLAG-GFP (pl-Dfg), was constructed and used to transfect packaged phoenix cells. The supernatant containing recombinant retroviral particles from the transfected phoenix cells was harvested and utilized to infect target 9L cells. The cytotoxic oxidative stress of infected 9L cells was induced by the DAAO substrate, D-alanine. The plasmid pl-Dfg was successfully constructed. The high titer retroviral supernatant was obtained from the transfected phoenix cells. Infected 9L cells were less viable after exposure to D-alanine compared to the control group. Anti-apoptotic proteins significantly inhibited cell death. The DAAO/D-alanine system has a potential utility for gene therapy and may be an effective strategy for the treatment of brain cancer and other malignant tumors.
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PMID:Transfection of the DAAO gene and subsequent induction of cytotoxic oxidative stress by D-alanine in 9L cells. 1863 95

The poor and aberrant vascularization of solid tumors makes them susceptible to localized areas of oxygen deficiency that can be considered sites of tumor vulnerability to prodrugs that are preferentially activated to cytotoxic species under conditions of low oxygenation. To readily facilitate the selection of agents targeted to oxygen-deficient cells in solid tumors, we have developed a simple and convenient two-enzyme system to generate oxygen deficiency in cell cultures. Glucose oxidase is employed to deplete oxygen from the medium by selectively oxidizing glucose and reducing molecular oxygen to hydrogen peroxide; an excess of catalase is also used to scavenge the peroxide molecules. Rapid and sustained depletion of oxygen occurs in medium or buffer, even in the presence of oxygen at the liquid/air interface. Studies using CHO/AA8 Chinese hamster cells, EMT6 murine mammary carcinoma cells, and U251 human glioma cells indicate that this system generates an oxygen deficiency that produces activation of the hypoxia-targeted prodrug KS119. This method of generating oxygen deficiency in cell culture is inexpensive, does not require cumbersome equipment, permits longer incubation times to be used without the loss of sample volume, and should be adaptable for high-throughput screening in 96-well plates.
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PMID:Generation of oxygen deficiency in cell culture using a two-enzyme system to evaluate agents targeting hypoxic tumor cells. 1895 66

Atomic force microscopy (AFM), malondialdehyde (MDA) assays, and amperometric measurements of extracellular hydrogen peroxide (H(2)O(2)) were used to test the hypothesis that graded hyperoxia induces measurable nanoscopic changes in membrane ultrastructure and membrane lipid peroxidation (MLP) in cultured U87 human glioma cells. U87 cells were exposed to 0.20 atmospheres absolute (ATA) O(2), normobaric hyperoxia (0.95 ATA O(2)) or hyperbaric hyperoxia (HBO(2), 3.25 ATA O(2)) for 60 min. H(2)O(2) (0.2 or 2 mM; 60 min) was used as a positive control for MLP. Cells were fixed with 2% glutaraldehyde immediately after treatment and scanned with AFM in air or fluid. Surface topography revealed ultrastructural changes such as membrane blebbing in cells treated with hyperoxia and H(2)O(2). Average membrane roughness (R(a)) of individual cells from each group (n=35 to 45 cells/group) was quantified to assess ultrastructural changes from oxidative stress. The R(a) of the plasma membrane was 34+/-3, 57+/-3 and 63+/-5 nm in 0.20 ATA O(2), 0.95 ATA O(2) and HBO(2), respectively. R(a) was 56+/-7 and 138+/-14 nm in 0.2 and 2 mM H(2)O(2). Similarly, levels of MDA were significantly elevated in cultures treated with hyperoxia and H(2)O(2) and correlated with O(2)-induced membrane blebbing (r(2)=0.93). Coapplication of antioxidant, Trolox-C (150 microM), significantly reduced membrane R(a) and MDA levels during hyperoxia. Hyperoxia-induced H(2)O(2) production increased 189%+/-5% (0.95 ATA O(2)) and 236%+/-5% (4 ATA O(2)) above control (0.20 ATA O(2)). We conclude that MLP and membrane blebbing increase with increasing O(2) concentration. We hypothesize that membrane blebbing is an ultrastructural correlate of MLP resulting from hyperoxia. Furthermore, AFM is a powerful technique for resolving nanoscopic changes in the plasma membrane that result from oxidative damage.
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PMID:Acute hyperoxia increases lipid peroxidation and induces plasma membrane blebbing in human U87 glioblastoma cells. 1935 85

Accumulation of reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O(2)) is an oxidative stress response, which induced various defense mechanisms or programmed cell death (PCD). As one of the major types of PCD, autophagy has been observed in response to several anticancer drugs and demonstrated to be responsible for cell death. To date, however, the exact mechanism by which ROS regulates autophagy is still poorly understood. Thus, the purposes of this study were to elucidate how H(2)O(2) exerts its cytotoxic effects on malignant glioma U251 cells and to uncover the molecular mechanism that might be involved. Here, we show that H(2)O(2)-induced autophagy and apoptosis in U251 cells are mediated through the Beclin 1 and Akt/mTOR pathways. Accumulation of ROS leads to changes in mitochondrial permeability with loss of mitochondrial membrane potential and disruption of mitochondrial dynamics at a transcriptional level of fission and fusion. Overexpression of cellular Bcl-2 partially inhibited autophagy through both the Beclin 1 and the Akt/mTOR pathways and led to recovery of mitochondrial dynamics. When autophagy was prevented at an early stage by 3-methyladenine, apoptosis significantly increased. Our data provide the first evidence that H(2)O(2) induces autophagy through interference with the Beclin 1 and Akt/mTOR signaling pathways and is regulated by the anti-apoptotic gene Bcl-2 in glioma U251 cells.
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PMID:Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. 1945 Nov 93

The aim of our study was to evaluate the role of proton magnetic resonance (MR) spectroscopy and MR perfusion in the follow-up of low-grade gliomas, since conventional MR imaging (MRI) is not reliable in detecting the passage from a low- to high-grade tumor. Twenty-one patients with a World Health Organisation (WHO) grade II glioma were followed up using proton MR spectroscopy, perfusion, and conventional MRIs. Follow-up MRIs had been performed at the third month of evolution and then twice a year, with an average of five MR studies per patient. Five out of the 21 patients had an anaplastic transformation. A choline to creatine ratio (choline/creatine ratio) above 2.4 is associated with an 83% risk of a malignant transformation in an average delay of 15.4 months. The choline/creatine ratio at this threshold was more efficient than perfusion MR in detecting the anaplastic transformation, with sensitivity of 80% and specificity of 94%. An increased choline/creatine ratio seemed to occur an average 15 months before the elevation of relative cerebral blood volume (rCBV). The mean annual growth of low-grade glioma was 3.65 mm. A growth rate higher than 3 mm per year was also correlated with greater risk of anaplastic transformation. Proton magnetic resonance spectroscopy should be recommended in the follow-up of low-grade gliomas since the choline/creatine ratio can predict anaplastic transformation before perfusion abnormalities, with high positive predictive value of 83%.
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PMID:Predictive value of multimodality MRI using conventional, perfusion, and spectroscopy MR in anaplastic transformation of low-grade oligodendrogliomas. 1972 62

The metabolic behavior of complex brain tumors, like Gliomas and Meningiomas, with respect to their type and grade was investigated in this paper. Towards this direction the smallest set of the most representative metabolic markers for each brain tumor type was identified, using ratios of peak areas of well established metabolites, from (1)H-MRSI (Proton Magnetic Resonance Spectroscopy Imaging) data of 24 patients and 4 healthy volunteers. A feature selection method that embeds Fisher's filter criterion into a wrapper selection scheme was applied; Support Vector Machine (SVM) and Least Squares-SVM (LS-SVM) classifiers were used to evaluate the ratio markers classification significance. The area under the Receiver Operating Characteristic curve (AUROC) was adopted to evaluate the classification significance. It is found that the NAA/CHO, CHO/S, MI/S ratios can be used to discriminate Gliomas and Meningiomas from Healthy tissue with AUROC greater than 0.98. Ratios CHO/S, CRE/S, MI/S, LAC/CRE, ALA/CRE, ALA/S and LIPS/CRE can identify type and grade differences in Gliomas giving AUROC greater than 0.98 apart from the scheme of Gliomas grade II vs grade III where 0.84 was recorded due to high heterogeneity. Finally NAA/CRE, NAA/S, CHO/S, MI/S and ALA/S manage to discriminate Gliomas from Meningiomas providing AUROC exceeding 0.90.
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PMID:Revealing the metabolic profile of brain tumors for diagnosis purposes. 1996 7


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