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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavonoids are a broadly distributed class of plant pigments, universally present in plants. They are strong anti-oxidants that can inhibit carcinogenesis in rodents. Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound extracted from many plants, honey, and propolis. It possesses potent anti-inflammatory, anti-oxidant properties, promotes cell death, and perturbing cell cycle progression. However, the mechanism by which chrysin inhibits cancer cell growth remains poorly understood. Therefore, we developed an interest in the relationship between MAPK signaling pathways and cell growth inhibition after chrysin treatment in rat C6 glioma cells. Cell viability assay and flow cytometric analysis suggested that chrysin exhibited a dose-dependent and time-dependent ability to block rat C6 glioma cell line cell cycle progression at the G1 phase. Western blotting analysis showed that the levels of Rb phosphorylation in C6 glioma cells exposed to 30 microM chrysin for 24h decreased significantly. We demonstrated the expression of cyclin-dependent kinase inhibitor, p21(Waf1/Cip1), to be significantly increased, but the p53 protein level did not change in chrysin-treated cells. Both cyclin-dependent kinase 2 (CDK2) and 4 (CDK4) kinase activities were reduced by chrysin in a dose-dependent manner. Furthermore, chrysin also inhibited proteasome activity. We further showed that chrysin induced p38-MAPK activation, and using a specific p38-MAPK inhibitor, SB203580, attenuated chrysin-induced p21(Waf1/Cip1) expression. These results suggest that chrysin exerts its growth-inhibitory effects either through activating p38-MAPK leading to the accumulation of p21(Waf1/Cip1) protein or mediating the inhibition of proteasome activity.
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PMID:Chrysin induces G1 phase cell cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1 expression: involvement of p38 mitogen-activated protein kinase. 1586 44

Thallium acetate is a known neurotoxic agent. In this study, we investigated the mechanisms by which thallium acetate induces cell cycle arrest and cell apoptosis in cultured LC6 glioma cells. Exposure of C6 glioma cells to thallium acetate decreased cell viability as demonstrated by the MTT assay. Incubation of thallium acetate arrested cell cycle progression at the G2/M phase and caused cellular apoptosis at 300 microM as determined by trypan blue exclusion and flow cytometric analysis. The G2/M arrest was associated with a decrease in expression of CDK2 protein and an upregulation of p53 and the CDK inhibitor p21(Cip1), but not p27(Kip1). Thallium acetate did not alter the protein levels of cyclin A and B; cyclin D1, D2, and D3; and CDK4 expression in C6 glioma cells. Incubation of C6 glioma cells with thallium acetate upregulated the expression of proapoptotic proteins Bad and Apaf and downregulated the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. In conclusion, these data suggest that thallium acetate inhibits cell cycle progression at G2/M phase by suppressing CDK activity through the p53-mediated induction of the CDK inhibitor p21(Cip1). Impairment of cell cycle progression may trigger the activation of a mitochondrial pathway and shifts the balance in the Bcl-2 family toward the proapoptotic members, promoting the formation of the apoptosome and, consequently, apoptosis.
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PMID:Thallium acetate induces C6 glioma cell apoptosis. 1596 99

Glioma, and in particular high-grade astrocytoma termed glioblastoma multiforme (GBM), is the most common primary tumor of the brain. Primarily because of its diffuse nature, there is no effective treatment for GBM, and relatively little is known about the processes by which it develops. Therefore, in order to design novel therapies and treatments for GBM, research has recently intensified to identify the cellular and molecular mechanisms leading to GBM formation. Modeling of astrocytomas by genetic manipulation of mice suggests that deregulation of the pathways that control gliogenesis during normal brain development, such as the differentiation of neural stem cells (NSCs) into astrocytes, might contribute to GBM formation. These pathways include growth factor-induced signal transduction routes and processes that control cell cycle progression, such as the p16-CDK4-RB and the ARF-MDM2-p53 pathways. The expression of several of the components of these signaling cascades has been found altered in GBM, and recent data indicate that combinations of mutations in these pathways may contribute to GBM formation, although the exact mechanisms are still to be uncovered. Use of novel techniques including large-scale genomics and proteomics in combination with relevant mouse models will most likely provide novel insights into the molecular mechanisms underlying glioma formation and will hopefully lead to development of treatment modalities for GBM.
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PMID:Molecular mechanisms in gliomagenesis. 1609 98

The disparate lengths of survival among patients with malignant astrocytic gliomas (anaplastic astrocytomas [AAs] and glioblastoma multiforme [GBM]) cannot be adequately accounted for by clinical variables (patient age, histology, and recurrent status). Using real-time quantitative reverse transcription-polymerase chain reaction, we quantified the expression of four genes that were putative prognostic markers (CDK4, IGFBP2, MMP2, and RPS9) in a set of 43 AAs, 41 GBMs, and seven adjacent normal brain tissues. We previously explicated the expression and prognostic value of PAX6, PTEN, VEGF, and EGFR in these glioma tissues and established a comprehensive prognostic model (Zhou et al., 2003). This study attempts to improve that model by including four additional genetic markers, which exhibited a differential expression (P < 0.001) among tumor grades and between tumor and normal tissues. By including eight log-scaled gene expression variables, three clinical variables, and interaction terms among the eight genes, we established a prognostic model that accounted for two thirds of the variation (R2) in survival for this set of patients. To improve the R2 of the model without compromising its clinical utility, our data demonstrated that incorporating genes from different pathways markedly strengthens the model. Spearman rank correlation analysis of gene expression demonstrated a statistically significant positive correlation (P < 0.01) between the expression of IGFBP2-MMP2 and IGFBP2-VEGF in GBMs, but not in AAs. This finding suggests that the expression of IGFBP2 is associated with pathways activated specifically in GBMs that result in enhancing invasiveness and angiogenesis.
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PMID:Modeling prognosis for patients with malignant astrocytic gliomas: quantifying the expression of multiple genetic markers and clinical variables. 1621 13

ZD1839 ("Iressa") is an orally active, selective epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor. We evaluated the antitumor activity of ZD1839 in combination with HSP90 antagonist, 17-AAG in malignant human glioma cell lines. ZD1839 independently produced a dose-dependent inhibition of cellular proliferation in glioma cells grown in culture with time- and dose-dependent accumulation of cells in G(1) phase of the cell cycle on flow cytometric analysis, although the concentrations required for optimal efficacy were at or above the limits of clinically achievable levels. Because the heat shock protein (HSP) is involved in the conformational maturation of a number of signaling proteins critical to the proliferation of malignant glioma cells, we hypothesized that the HSP90 inhibitor 17-AAG would potentiate ZD 1839-mediated glioma cytotoxicity by decreasing the activation status of EGF receptor, as well as down regulating the levels of other relevant signaling effectors. We, therefore, examined the effects of ZD1839 and 17-AAG, alone and in combination, on signal transduction and apoptosis in a series of malignant glioma cell lines. Simultaneous exposure to these inhibitors significantly induced cell death and quantitative analysis revealed that interaction between ZD1839 and 17-AAG-induced cytotoxicity was synergistic, leading to a pronounced increase in active caspase-3 and PARP cleavage. No significant growth inhibition or caspase activation was seen in control cells. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and a significant downregulation of EGFR receptor, Raf-1 and mitogen activated protein kinase (MAPK). Cells exposed to 17-AAG and ZD1839 displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that ZD1839, an EGF receptor tyrosine kinase inhibitor, plays a critical role in regulating the apoptotic response to 17-AAG and that multi-site targeting of growth signaling and cell survival pathways could provide a potent strategy to treat patients with malignant gliomas.
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PMID:Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth. 1655 Jun 10

Staurosporine was found to bring about complete growth inhibition of human glioma cell lines. U87 MG cells were arrested in S phase while U373 MG cells in G2/M phase on staurosporine treatment. Consistent with this observation, no change in G1 phase regulators viz., Cyclin D1, D3 and CDK4 was seen on staurosporine treatment. The levels of CDK2, CDC2, Cyclin A and Cyclin B proteins decreased, while the levels of CDK inhibitors viz., p21 and p27 were found to increase on staurosporine treatment. The mRNA levels of CDK2 and CDC2 genes were also found to decrease on staurosporine treatment. Thus apart from staurosporine's known direct inhibitory effect on CDK2 and CDC2 activities, staurosporine was found to down-regulate activities of these two kinases by modulating the expression of the kinases themselves as well that of their activating partners (Cyclins) and their inhibitors.
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PMID:Staurosporine-induced growth inhibition of glioma cells is accompanied by altered expression of cyclins, CDKs and CDK inhibitors. 1677 Jul 40

High-grade gliomas comprise the most malignant type of primary brain tumor and are relatively frequent in adults. Recent studies have indicated that the loss of p16, an inhibitor of CDK4, promotes the acquisition of malignant characteristics in gliomas. A correlation between overexpression of urokinase-type plasminogen activator receptor (uPAR) and glioblastoma invasion has also been established. Moreover, uPAR/integrin binding has been shown to initiate or potentiate integrin signaling through focal adhesion kinase and/or src kinases. Our previous studies demonstrated that downregulation of uPAR expression and restoration of p16 regress glioma growth in nude mice and downregulate alphavbeta3 integrin receptor expression. Here, we show the effect of a bicistronic construct on alphavbeta5 integrin receptor expression, angiogenesis and the biochemical pathway that causes glioma cell death. The U251 glioblastoma and a glioblastoma xenograft cell line transduced with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 and antisense RNA of uPAR significantly inhibited human mammary epithelial cell capillary formation and vascular endothelial growth factor (VEGF) expression. Inactivation of anti-apoptotic molecules such as Akt, PARP, activation of caspases and accumulation of heteroduplex chromosomal DNA in pre-G1 phase of the cell cycle was demonstrated by Western blotting, caspase activity assay and FACS analysis. Nuclear DNA fragmentation upon induction of apoptosis was scored using the TUNEL assay. Significant downregulation of alphavbeta5 integrin receptor expression was also confirmed by FACS analysis, immunoprecipitation and RT-PCR. Taken together, the results demonstrate that the sense p16 and anti-sense uPAR bicistronic construct significantly inhibits angiogenesis, induces apoptosis by deregulation of the PI3K-Akt pathway and downregulates alphavbeta5 integrin receptor expression.
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PMID:Sense p16 and antisense uPAR bicistronic construct inhibits angiogenesis and induces glioma cell death. 1727 68

To further understand the biological significance of amplifications for glioma development and recurrencies, we characterized amplicon frequency and size in low-grade glioma and amplicon stability in vivo in recurring glioblastoma. We developed a 12q13-21 amplicon-specific genomic microarray and a bioinformatics amplification prediction tool to analyze amplicon frequency, size, and maintenance in 40 glioma samples including 16 glioblastoma, 10 anaplastic astrocytoma, 7 astrocytoma WHO grade 2, and 7 pilocytic astrocytoma. Whereas previous studies reported two amplified subregions, we found a more complex situation with many amplified subregions. Analyzing 40 glioma, we found that all analyzed glioblastoma and the majority of pilocytic astrocytoma, grade 2 astrocytoma, and anaplastic astrocytoma showed at least one amplified subregion, indicating a much higher amplification frequency than previously suggested. Amplifications in low-grade glioma were smaller in size and displayed clearly different distribution patterns than amplifications in glioblastoma. One glioblastoma and its recurrencies revealed an amplified subregion of 5 Mb that was stable for 6 years. Expression analysis of the amplified region revealed 10 overexpressed genes (i.e., KUB3, CTDSP2, CDK4, OS-9, DCTN2, RAB3IP, FRS2, GAS41, MDM2, and RAP1B) that were consistently overexpressed in all cases that carried this amplification. Our data indicate that amplifications on 12q13-21 (a) are more frequent than previously thought and present in low-grade tumors and (b) are maintained as extended regions over long periods of time.
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PMID:A different view on DNA amplifications indicates frequent, highly complex, and stable amplicons on 12q13-21 in glioma. 1840 36

Recent studies have suggested that the proliferation of malignant gliomas may result from activation of protein kinase C (PKC)-mediated pathways. Enzastaurin (LY317615), an acyclic bisindolylmaleimide, is an oral inhibitor of PKCbeta as well as other isoforms. The initial objective of this study was to assess the efficacy of enzastaurin in a series of malignant human glioma cell lines with diverse genomic alterations. Although enzastaurin independently produced a dose-dependent inhibition of cellular proliferation and decreased cell viability in each of the glioma cell lines examined, and partially down-regulated Akt and GSK3beta phosphorylation, median effective concentrations were at the upper limits of, or above, the clinically achievable range in all cell lines tested. We therefore examined whether the efficacy of enzastaurin could be enhanced by combination with the HSP90 antagonist, 17-AAG, which inhibits Akt and other signaling intermediates by a distinct mechanism. In comparison to the effect of enzastaurin alone, combination of enzastaurin with 17-AAG led to marked enhancement of antiproliferative and cytotoxic effects. Simultaneous exposure to both agents significantly increased the release of cytochrome c, as well as caspase 3 activation, Bax cleavage, and inhibition of Akt phosphorylation. Cells exposed to enzastaurin and 17-AAG also displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that the efficacy of enzastaurin can be potentiated by the addition of 17-AAG, and indicate that combining molecularly targeted therapies may provide a more effective strategy than single-agent therapy to treat patients with malignant gliomas.
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PMID:The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells. 1846 65

We performed genotyping and exon-level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low-copy number amplifications (2.5 < n < 7) and high-copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high-copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5'-3' expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes.
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PMID:Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1-SLC12A1 fusion gene. 2019 86


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