Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS) from Gram-negative bacterial has been identified as an important molecule involved in the inflammatory process through inducing nitric oxide (NO) production. However, the effect of LPS in carcinogenesis is still undefined. In the present study, the biological effect of LPS was examined in 12-o-tetradecanoylphorbol 13-acetate (TPA)-treated rat glioma cells C6. Results of MTT assay showed that LPS and TPA exhibited no significant cytotoxicity in glioma C6 cells. Interestingly, transformation foci were found in LPS/TPA-treated glioma C6 cells, but not in LPS- or TPA-treated cells. The transformation foci induced by LPS/TPA were also observed in the absence of serum. It indicates that induction of transformation foci formation by LPS and TPA is independent on the serum in glioma C6 cells. Induction of iNOS gene expression and NO production was examined in LPS/TPA-treated cells, but not obvious in LPS- or TPA-treated cells. NO donor sodium nitroprusside (SNP) induces transformation in glioma C6 cells in according with elevating NO production. In addition, LPS/TPA induces metalloproteinase 9 (MMP9) activity by gelatin activity assay in gel. Wogonin and quercetin but not rutin, inhibitors of iNOS gene expression and NO production induced by LPS, showed the significant inhibition on LPS/TPA-induced transformation foci formation, accompanied by inhibiting iNOS gene expression, NO production and MMP9 activity. Results of the present study provide scientific evidences to link the inflammatory responses and carcinogenesis, and suggest that NO derived from inflammation may contribute to the progression of carcinogenesis; natural products with anti-inflammatory effects such as wogonin and quercetin possess the ability to block transformation induced by LPS/TPA.
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PMID:Lipopolysaccharide enhancement of 12-o-tetradecanoylphorbol 13-acetate-mediated transformation in rat glioma C6, accompanied by induction of inducible nitric oxide synthase. 1470 May 23

Prostaglandin H synthase (PHS) is a key enzyme in the synthesis of prostaglandins (PGs). Recently, enhanced expression of PHS-2 in brain tumors and the correlation between the PHS-2 level and the histopathological grade of glioma has been reported. Furthermore, in vitro inhibition of glioma cell growth by a specific PHS-2 inhibitor, NS398, has been demonstrated. It has also been shown that prostaglandin E2 (PGE2) contributes to colon carcinogenesis by binding to the prostaglandin E receptor subtype EP1. We therefore evaluated the effects of NS398 and two EP1 antagonists, SC51089 and AH6809, on glioma cell lines. To evaluate mechanisms of NS398's action, two glioma cell lines, a PHS-2-positive cell line (KMG4) and a PHS-2-deficient cell line (A 172), were used. NS398 inhibited both the anchorage-dependent and -independent growth of glioma cell lines regardless of PHS-2 expression, suggesting that some PHS-2-independent mechanisms underlie the antineoplastic effect of NS398. However, the antineoplastic effect was attenuated by the addition of PGE2, which is one of the main products of PHS, suggesting the predominant mechanism is PHS-dependent. The EP1 antagonists, SC51089 and AH6809, inhibited the growth of glioma cell lines in vitro. Furthermore, NS398 or SC51089 slowed tumor growth in vivo, which was assessed using KMG4 tumor xenografts on SCID mice. PHS-2 inhibitors and EP1 antagonists might be useful in the prevention and/or treatment of glioma.
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PMID:Inhibition of human glioma cell growth by a PHS-2 inhibitor, NS398, and a prostaglandin E receptor subtype EP1-selective antagonist, SC51089. 1501 58

High frequencies of loss of heterozygosity (LOH) on chromosome 10p14-p15 have been reported in various tumors, including glioma, pulmonary carcinoid and cervical, hepatic and prostatic carcinomas. These findings suggest the presence of a tumor suppressor gene at the loci. However, analysis of LOH on chromosome 10p14-p15 in esophageal tumors has not been reported. Therefore, we examined LOH on chromosome 10p14-p15 in 88 esophageal squamous cell carcinomas (SCC) (35 superficial- and 53 advanced-types) and 44 dysplasias by microsatellite assay. Five oligonucleotide primer sets for microsatellite loci D10S191, D10S501, D10S559, D10S558 and D10S249 were used. In dysplasias, frequent LOH was detected with markers D10S191 (26%) and D10S249 (33%). In superficial esophageal SCCs, frequent LOH was detected with markers D10S191 (26%), D10S559 (50%), D10S558 (29%) and D10S249 (33%). In advanced esophageal SCCs, we found frequent LOH was detected with markers D10S191 (38%), D10S501 (25%) and D10S559 (30%). There were no significant correlations between LOH on chromosome 10p14-p15 and clinicopathologic features, including patient age, sex, tumor location, depth of invasion and lymph node metastasis. These data suggest that a putative tumor suppressor gene for esophageal carcinogenesis may be located on chromosome 10p14-p15 and that malfunction of this gene may be involved in the development but not progression of esophageal tumors.
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PMID:Frequent loss of heterozygosity on chromosome 10p14-p15 in esophageal dysplasia and squamous cell carcinoma. 1525 98

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

Mitochondrial benzodiazepine-receptor (mBzR) ligands constitute a heterogeneous class of compounds that show a pleiotropic spectrum of effects within the cells, including the modulation of apoptosis. In this paper, a novel synthetic 2-phenylindol-3-ylglyoxylamide derivative, N,N-di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide (PIGA), which shows high affinity and selectivity for the mBzR, is demonstrated to induce apoptosis in rat C6 glioma cells. PIGA was able to dissipate mitochondrial transmembrane potential (DeltaPsim) and to cause a significant cytosolic accumulation of cytochrome c. Moreover, typical features of apoptotic cell death, such as caspase-3 activation and DNA fragmentation, were also detected in PIGA-treated cells. Our data expand the knowledge on mBzR ligand-mediated apoptosis and suggest PIGA as a novel proapoptotic compound with therapeutic potential against glial tumours, in which apoptosis resistance has been reported to be involved in carcinogenesis.
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PMID:PIGA (N,N-Di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide), a new mitochondrial benzodiazepine-receptor ligand, induces apoptosis in C6 glioma cells. 1588 77

Chemokines have been found to alter tumor growth and metastasis. We have described previously that a particular chemokine receptor, CXCR4, was predominantly expressed on various glioma cell lines and in resected glioblastoma specimens. Herein, we have tested the ligand of CXCR4, stromal cell derived factor-1alpha (SDF-1alpha, CXCL12), on the response of human glioma cells. We found that SDF-1alpha increased the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), but not the other MT-MMPs, MMP-2 or MMP-9. The SDF-1alpha enhanced MT2-MMP expression was blocked by a CXCR4 antagonist, AMD3100. Functional invasion assays showed that SDF-1alpha stimulated glioma cells to invade through matrigel-coated chambers and this effect was inhibited in glioma cells by the stable downregulation of MT2-MMP expression using small interfering RNA (siRNA). In vivo and at asymptomatic stages following intracerebral implant of cells, mice harboring MT2-MMP siRNA downregulated clones had smaller and less invasive tumors compared with mice implanted with non-specific siRNA control cells. Analyses at symptomatic stages demonstrate that mice with MT2-MMP siRNA clones survive longer than mice harboring control cells. These results highlight MT2-MMP as an effector of CXCR4 signaling in glioma cells, and they reveal the novel role of MT2-MMP in modulating tumor activity.
Carcinogenesis 2005 Dec
PMID:The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. 1603 74

The chemokine GRO-alpha (CXCL1) has been found to mediate the proliferation of glia progenitor cells during neural development. As malignant gliomas are thought to arise from glia progenitors or their differentiated counterparts, astrocytes or oligodendrocytes, we have investigated whether GRO-alpha regulates the tumor characteristics of glioma cells. We found first that resected glioma specimens were strongly immunoreactive for GRO-alpha expression in cells with the morphology of tumor cells. In culture, the U251 glioma line transfected to overexpress GRO-alpha had elevated levels of motility and invasiveness. GRO-alpha transfectants increased their expression of several proteins associated with migratory behavior, including matrix metalloproteinase-2, beta1-integrin and SPARC. The implantation of GRO-alpha glioma clones into the brain of nude mice caused the early demise of mice and this was associated with the formation of larger intracerebral tumors when compared with mice implanted with vector control lines. These results implicate GRO-alpha in gliomas and suggest that the dysregulation of a glia proliferative factor contributes to tumorigenesis. Targeting GRO-alpha may be a useful therapeutic tool to control brain tumor biology.
Carcinogenesis 2005 Dec
PMID:The chemokine GRO-alpha (CXCL1) confers increased tumorigenicity to glioma cells. 1603 75

N-nitroso compounds (NOC) have been associated with carcinogenesis in a wide range of species, including humans. There is strong experimental data showing that nitrosamides (R(1)NNO.COR(2)), a type of NOC, are potent neuro-carcinogens when administered transplacentally. Some medications are a concentrated source of amides or amines, which in the presence of nitrites under normal acidic conditions of the stomach can form NOC. Therefore, these compounds, when ingested by women during pregnancy, may be important risk factors for tumors of the central nervous system in the offspring. The aim of the present study was to test the association between maternal use of medications that contain nitrosatable amines or amides and risk of primary childhood brain tumors (CBT). A case-control study was conducted, which included 1,218 cases and 2,223 population controls, recruited from 9 centers across North America, Europe and Australia. Analysis was conducted for all participants combined, by tumor type (astroglial, primitive neuroectodermal tumors and other glioma), and by age at diagnosis (< or =5 years; >5 years). There were no significant associations between maternal intake of medication containing nitrosatable amines or amides and CBT, for all participants combined and after stratification by age at diagnosis and histological subtype. This is the largest case-control study of CBT and maternal medications to date. Our data provide little support for an association between maternal use of medications that may form NOC and subsequent development of CBT in the offspring.
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PMID:Maternal medication use and the risk of brain tumors in the offspring: the SEARCH international case-control study. 1616 Oct 45

EFA6A, or Pleckstrin and Sec7 domain protein, is a member of guanine nucleotide exchange factors for ADP ribosylation factor 6 (ARF6). Whereas EFA6A is specifically expressed in the brain, little is known about its function in glial cells or glioma. Here we show that elevated EFA6A expression is detectable in both low-grade and high-grade human glioma tissues samples. To investigate the role of EFA6A in glioma carcinogenesis, we generated a human glioblastoma cell line which conditionally overexpresses EFA6A (U373-EFA6A). We showed that overexpression of EFA6A had no effect on cell proliferation, apoptosis, or cell cycle control. However, as shown by wound healing and in vitro cell invasion assays, it significantly enhanced the cell motility and invasiveness whereas silencing EFA6A by its dominant negative mutant EFA6A(E242K) produced opposite effects. We further showed that ARF6/extracellular signal-regulated kinase (ERK) signaling is required for the EFA6A-mediated cell invasion because both EFA6A(E242K) and ARF6 dominant negative mutant ARF6(T27N) markedly reduced the phosphorylated ERK level and EFA6A-mediated invasive capacity. Consistently, mitogen-activated protein kinase/ERK kinase inhibitor U0126 could abolish the EFA6A-induced cell invasion. These results suggest for the first time a potential role of EFA6A/ARF6/ERK signal cascade in glioma cell migration and invasion.
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PMID:EFA6A enhances glioma cell invasion through ADP ribosylation factor 6/extracellular signal-regulated kinase signaling. 1645 16

N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid is under clinical evaluation as a therapeutic agent in a variety of cancers. Its mechanism(s) of action involves multiple overlapping pathways that still remain unclear. In glioma cells its mechanism of action is not well elucidated. Here, we show that 4-HPR and not all-trans retinoic acid and 9-cis retinoic acid effectively induce apoptosis in glioma cells. 4-HPR-induced apoptosis is associated with hydroperoxide production and loss of mitochondrial membrane potential (Delta Psi(m)). Ultrastructural changes further indicate 4-HPR-induced mitochondrial swelling, endoplasmic reticulum (ER) dilation as well as close proximity of mitochondria and ER. As suggested by dilated ER, 4-HPR treatment increased the free cytosolic Ca(2+) as well as mitochondrial Ca(2+). Chelation of extracellular Ca(2+) by EGTA did not prevent Ca(2+) elevation, thus suggesting involvement of intracellular calcium stores in the release. Buffering of intracellular calcium by BAPTA-AM did not prevent 4-HPR-induced apoptosis; however, blocking the release of Ca(2+) from ER by heparin inhibited apoptosis, indicating the role of depletion of Ca(2+) from ER stores in apoptosis. 4-HPR treatment also resulted in an increase in Bax levels along with its translocation to mitochondria that promote mitochondrial membrane permeabilization. 4-HPR-induced apoptosis was further associated with the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol and nucleus, respectively, along with caspase-3 and caspase-7 activation. However, AIF nuclear translocation, peripheral chromatin condensation and apoptosis were not completely prevented by general caspase inhibitors, thus suggesting involvement of a caspase-dependent and caspase-independent pathway in 4-HPR-induced apoptosis. Taken together, these results suggest the role of mitochondrial-mediated pathway and ER stress as a key event in 4-HPR-induced apoptosis in glioma cells.
Carcinogenesis 2006 Oct
PMID:Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress. 1667 69


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