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)

Exposure to environmental radiation and the application of new clinical modalities, such as radioimmunotherapy, have heightened the need to understand cellular responses to low dose and low-dose rate ionizing radiation. Many tumor cell lines have been observed to exhibit a hypersensitivity to radiation doses <50 cGy, which manifests as a significant deviation from the clonogenic survival response predicted by a linear-quadratic fit to higher doses. However, the underlying processes for this phenomenon remain unclear. Using a gel microdrop/flow cytometry assay to monitor single cell proliferation at early times postirradiation, we examined the response of human A549 lung carcinoma, T98G glioma, and MCF7 breast carcinoma cell lines exposed to gamma radiation doses from 0 to 200 cGy delivered at 0.18 and 22 cGy/min. The A549 and T98G cells, but not MCF7 cells, showed the marked hypersensitivity at doses <50 cGy. To further characterize the low-dose hypersensitivity, we examined the influence of low-dose radiation on cell cycle status and apoptosis by assays for active caspase-3 and phosphatidylserine translocation (Annexin V binding). We observed that caspase-3 activation and Annexin V binding mirrored the proliferation curves for the cell lines. Furthermore, the low-dose hypersensitivity and Annexin V binding to irradiated A549 and T98G cells were eliminated by treating the cells with pifithrin, an inhibitor of p53. When p53-inactive cell lines (2800T skin fibroblasts and HCT116 colorectal carcinoma cells) were examined for similar patterns, we found that there was no hyperradiosensitivity and apoptosis was not detectable by Annexin V or caspase-3 assays. Our data therefore suggest that low-dose hypersensitivity is associated with p53-dependent apoptosis.
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PMID:Low-dose radiation hypersensitivity is associated with p53-dependent apoptosis. 1549 30

Capsaicin induces apoptosis in some types of cells, but its mechanism remains obscure. In this study, peroxynitrite, a powerful oxidant generated from the reaction of superoxide and nitric oxide (NO) in biological system, was demonstrated to be responsible for capsaicin-mediated apoptosis in C6 glioma cells. Capsaicin-induced apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and also identified by Annexin V staining and comet assay. Capsazepine and ruthenium red, the vanilloid receptor 1 (VR1/TPRV1) antagonists, did not inhibit capsaicin-induced apoptosis. Exposure to capsaicin not only promoted the generation of superoxide and iNOS, but also markedly suppressed the expression of SODs. Nitrite and nitrate, the NO metabolites accumulated in the medium, and the nitrotyrosine was also increased in proteins of C6 glioma cells exposed to capsaicin. Pretreatment of cells with 4 microM ebselen (a peroxynitrite scavenger) showed effective inhibitory effect on the capsaicin-induced apoptosis. These results suggest that peroxynitrite can act as a potential mediator in the capsaicin-induced apoptosis in C6 glioma cells.
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PMID:Involvement of peroxynitrite in capsaicin-induced apoptosis of C6 glioma cells. 1568 Oct 35

Accumulating evidence suggests that glutamate plays a key role in the proliferation and invasion of glioblastoma tumors. Astrocytic tumors have been shown to release glutamate at high levels, which may stimulate tumor cell proliferation and motility via activation of glutamate receptors. Excess glutamate has also been found to facilitate tumor invasion by causing excitotoxic damage to normal brain thereby paving a pathway for tumor migration. Results from tissue microarray analyses showed decreased excitatory amino acid transporter-2 (EAAT-2) expression in high-grade glial tumors compared with low-grade astrocytomas and normal brain. EAAT-2 expression was inversely correlated with tumor grade, implicating its potential role in glial tumor progression, which was reflected by an undetectable level of EAAT-2 protein in glioma cell lines. In this study, we sought to investigate the effect of reconstituted EAAT-2 on glioma cell growth in vitro and in vivo by adenoviral-mediated gene transfer. Infection of glioma cells with Ad-EAAT-2 resulted in a physiologic level of functional EAAT-2, and a subsequent dose-dependent reduction in cell proliferation in all glioma cell lines tested compared with controls. Interestingly, results from analyses of Annexin V staining, detection of poly(ADP-ribose)polymerase cleavage and caspase-3 activation all indicated that Ad-EAAT-2 infection elicited apoptosis in glioma cells. Ex vivo experiments in nude mice showed a total suppression of tumor growth at sites that received Ad-EAAT-2-infected cells. Collectively, our results uncovered a new function of EAAT-2 in controlling glioma proliferation. Further studies will improve our knowledge of the role of glutamate in glioma growth and may provide useful prognostic information and alternative therapeutic targets for the treatment of glioma.
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PMID:The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. 1575 93

Therapeutic radiation and subsequent detection of tumor cell death has been performed mainly in vitro systems, making it difficult to accurately characterize the mechanisms of tumor cell death after radiosurgery. To better characterize what occurs to glioma cells after radiation therapy, we developed a rat model using the 9L gliosarcoma cell line implanted reproducibly to the caudate nucleus in rats. After 1 Gy radiation, 9L tumors in vivo induced mainly necrosis (determined by trypan blue exclusion) of 10 - 74 % at 6 - 72 hours post-radiation. This is in contrast to a previous in vitro study which demonstrated that 18 Gy of radiation induces considerably less cell death as determined by trypan blue exclusion (approximately 20 - 25 % at 6 - 72 hours post-radiation). However, significant amounts of apoptosis were detected as early as 6 hours after radiation. Apoptosis determination was by annexin V (marker of early apoptosis) and propidium iodide (marker of membrane stability) staining followed by flow cytometry detection. When caspase 3 and caspase 8 enzymatic activities (mediators of apoptosis) were measured from freshly explanted tumor cells, peak activity was found 6 hours after 1 Gy radiation (p < 0.01). Taken together, these data indicate the presence of apoptosis early after radiation therapy (1 Gy) which progressed to necrosis in a unique in vivo model of gliosarcoma that may prove useful in determining new therapeutic approaches to radiation therapy and tumor cell biology.
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PMID:Gliosarcoma cell death after radiosurgery in a rat model. 1601 90

The aim was to exploit simultaneous inhibition of glycolytic and pentose phosphate pathways of energy production for radiosensitization using 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) in transformed mammalian cells. Two human tumour cell lines (cerebral glioma, BMG-1 and squamous carcinoma cells 4197) were investigated. 2-DG and/or 6-AN added at the time of irradiation were present for 4 h after radiation. Radiation-induced cell death (macrocolony assay), cytogenetic damage (micronuclei formation), cell cycle delay (bromodeoxyuridne (BrdU) pulse chase), apoptosis (externalization of phosphotidylserine (PS) by annexin V), chromatin-bound proliferation cell nuclear antigen (PCNA) and cellular glutathione (GSH) levels were investigated as parameters of radiation response. The presence of 2-DG (5 mM) during and for 4 h after irradiation increased the radiation-induced micronuclei formation and cell death, and caused a time-dependent decrease in GSH levels in BMG-1 cells while no significant effects could be observed in 4197 cells. 6-AN (5 microM) enhanced the radiosensitivity of both cell lines and reduced the GSH content by nearly 50% in gamma-irradiated 4197 cells. Combining 2-DG and 6-AN caused a profound decrease in the GSH content and enhanced the radiation damage in both the cell lines by increasing mitotic and apoptotic cell death. Further, the combination (2-DG + 6-AN) enhanced the radiation-induced G2 block, besides arresting cells in S phase and inhibited the recruitment of PCNA. The combination of 2-DG and 6-AN enhances radiation damage by modifying damage response pathways and has the potential for improving radiotherapy of cancer.
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PMID:Radiosensitization by 6-aminonicotinamide and 2-deoxy-D-glucose in human cancer cells. 1607 55

In primary glioblastomas and other tumor types, the epidermal growth factor receptor (EGFR) is frequently observed with alterations, such as amplification, structural rearrangements, or overexpression of the gene, suggesting an important role in glial tumorigenesis and progression. In this study, we investigated whether posttranscriptional gene silencing by vector-mediated RNAi to inhibit EGFR expression can reduce the growth of cultured human gli36 glioma cells. To "knock down" EGFR expression, we have created HSV-1-based amplicons that contain the RNA polymerase III-dependent H1 promoter to express double-stranded hairpin RNA directed against EGFR at two different locations (pHSVsiEGFR I and pHSVsiEGFR II). We demonstrate that both pHSVsiEGFR I and pHSVsiEGFR II mediated knock-down of transiently transfected full-length EGFR or endogenous EGFR in a dose-dependent manner. The knock-down of EGFR resulted in the growth inhibition of human glioblastoma (gli36-luc) cells both in culture and in athymic mice in vivo. Cell cycle analysis and annexin V staining revealed that siRNA-mediated suppression of EGFR induced apoptosis. Overall HSV-1 amplicons can mediate efficient and specific posttranscriptional gene silencing.
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PMID:Herpes simplex virus 1 amplicon vector-mediated siRNA targeting epidermal growth factor receptor inhibits growth of human glioma cells in vivo. 1611 10

We describe an unusual form of non-accidental cell death marked by ectopic microtubules in the nucleus of a subpopulation of cisplatin-treated C6 glioma astrocytes in culture. At electron microscopy, the perinuclear condensed chromatin did not completely adhere to the nuclear envelope of these cells being separated by single or loosely bundled 20-nm-thick microtubules located in an electron-lucid slit-like zone; the presence of alpha-tubulin lining the inner membrane of the nuclear envelope was confirmed by immunolabeling at confocal microscopy. Since tufts of microfilaments-like fibers also occurred in their central nuclear areas, these cells are referred to as CIMMs (Cells with Intranuclear Microtubules and Microfilaments). The nuclear reorganization of CIMMs also involved nucleolar segregation and formation of heterogeneous ectopic ribonucleoprotein (RNP)-derived structures, indicating disruption of the RNP-based transcription machinery. The cytoplasmic organelles of CIMMs were structurally intact, and propidium iodide did not accumulate intracellularly under vital conditions while the plasma membrane was often Annexin V-positive. All these findings suggest that CIMMs were lethally damaged and committed to an atypical programmed cell death resembling early apoptosis (this is also supported by the presence of a limited number of TUNEL-positive CIMMs). CIMMs appeared well before the main cisplatin-induced cycling arrest of the cell population (G2/M block at 72 h) and had mostly G1 DNA content: this suggests that they may represent the cohort of cells which passed cisplatin-altered mitoses with intranuclear retention of microtubules from an incompletely disassembled mitotic spindle.
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PMID:Intranuclear microtubules are hallmarks of an unusual form of cell death in cisplatin-treated C6 glioma cells. 1628 54

We have shown that a COOH-terminal peptide of p53 (amino acids 361-382, p53p), linked to the truncated homeobox domain of Antennapedia (Ant) as a carrier for transduction, induced rapid apoptosis in human premalignant and malignant cell lines. Here, we report that human and rat glioma lines containing endogenous mutant p53 or wild-type (WT) p53 were induced into apoptosis by exposure to this peptide called p53p-Ant. The peptide was comparatively nontoxic to proliferating nonmalignant human and rat glial cell lines containing WT p53 and proliferating normal human peripheral marrow blood stem cells. Degree of sensitivity to the peptide correlated directly with the level of endogenous p53 expression and mutant p53 conformation. Apoptosis induction by p53p-Ant was quantitated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and Annexin V staining in human glioma cells in vitro and in a syngeneic orthotopic 9L glioma rat model using convection-enhanced delivery in vivo. The mechanism of cell death by this peptide was solely through the Fas extrinsic apoptotic pathway. p53p-Ant induced a 3-fold increase in extracellular membrane Fas expression in glioma cells but no significant increase in nonmalignant glial cells. These data suggest that p53 function for inducing Fas-mediated apoptosis in gliomas, which express sufficient quantities of endogenous mutant or WT p53, may be restored or activated, respectively, by a cell-permeable peptide derived from the p53 COOH-terminal regulatory domain (p53p-Ant). p53p-Ant may serve as a prototypic model for the development of new anticancer agents with unique selectivity for glioma cancer cells and it can be successfully delivered in vivo into a brain tumor by a convection-enhanced delivery system, which circumvents the blood-brain barrier.
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PMID:Restoration of p53 function for selective Fas-mediated apoptosis in human and rat glioma cells in vitro and in vivo by a p53 COOH-terminal peptide. 1643 59

The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C60) and water-soluble polyhydroxylated fullerene [C60(OH)n] were investigated. Crystal violet assay for cell viability demonstrated that nano-C60 was at least three orders of magnitude more toxic than C60(OH)n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V-fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C60 caused rapid (observable after few hours), reactive oxygen species (ROS)-associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C60(OH)n caused delayed, ROS-independent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C60 toxicity, but not C60(OH)n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C60(OH)n-induced apoptosis, but not nano-C60-mediated necrosis. Finally, C60(OH)n antagonized, while nano-C60 synergized with, the cytotoxic action of oxidative stress-inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.
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PMID:Distinct cytotoxic mechanisms of pristine versus hydroxylated fullerene. 1647 88

Mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) are activated in the majority of gliomas and contribute to tumor cell growth and survival. Sorafenib (Bay43-9006; Nexavar) is a dual-action Raf and vascular endothelial growth factor receptor inhibitor that blocks receptor phosphorylation and MAPK-mediated signaling and inhibits growth in a number of tumor types. Because our initial studies of this agent in a series of glioma cell lines showed only partial growth inhibition at clinically achievable concentrations, we questioned whether inhibition of PKC signaling using the PKC-delta inhibitor rottlerin might potentiate therapeutic efficacy. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with sorafenib and rottlerin as single agents or in combination. Sorafenib and rottlerin reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition. Flow-cytometric measurements of cells stained with Annexin V-propidium iodide and immunocytochemical assessment of cytochrome c and apoptosis-inducing factor release demonstrated that addition of rottlerin resulted in significantly higher levels of apoptosis than sorafenib alone. In addition, the combination of sorafenib and rottlerin reduced or completely inhibited the phosphorylation of extracellular signal-regulated kinase and Akt and down-regulated cell cycle regulatory proteins such as cyclin-D1, cyclin-D3, cyclin-dependent kinase (cdk)4, and cdk6 in a dose- and time-dependent manner. Our results clearly indicate that inhibition of PKC-delta signaling enhances the antiproliferative effect of sorafenib in malignant human glioma cell lines and support the examination of combinations of signaling inhibitors in these tumors.
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PMID:Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. 1695 60


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