UMLS:C0017638 - FACTA Search

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

The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21Waf1, Mdm2, and p27Kip1. Pretreatment with cycloheximide decreased the induction of cell death independently of p53 protein status, suggesting that the up-regulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis. Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-X(L), Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of delta(psi)m. Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the delta(psi)m disruption.
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PMID:Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. 998 1

Bcl-2 and bcl-xL are proteins known to inhibit cell death (apoptosis). Expression of these proteins in gangliogliomas has not been extensively examined. This study retrospectively evaluates bcl-2 and bcl-x immunostaining in paraffin-embedded materials in gangliogliomas. Twenty-nine gangliogliomas in 17 males and 12 females, age 2.5 to 47 years (mean, 20.7 years), were studied. Nineteen tumors were situated primarily in the temporal lobe. All but three patients presented with seizures ranging from 3 months to 28 years' duration (mean, 11.1 years) before surgery. All tumors histologically were comprised of an atypical neuronal component and a glioma component, which most frequently resembled a low-grade astrocytoma. Cortical dysplasia was observed adjacent to eight tumors. MIB-1 (marker of cell proliferation) labeling indices (percentage of positively staining tumor cell nuclei) ranged from 0 to 7.7 (mean, 0.8). bcl-2 staining was observed in 25 tumors (86%); neuronal staining was present in 24 cases (83%), and glial cell staining in 21 tumors (72%). Bcl-xL staining was only observed in eight gangliogliomas (28%); in all eight tumors (28%), neuronal staining was seen, and focal glial cell staining was present in two cases (7%). Four tumors (14%) did not stain with either bcl-2 or bcl-xL. There appeared to be no relationship between MIB-1 immunostaining and staining with bcl-2 or bcl-xL. bcl-2 expression by immunohistochemistry was observed more frequently than bcl-xL in gangliogliomas. Expression of these proteins may reflect abnormalities of apoptosis, which could play a role in the survival of cells that may be involved in the development of gangliogliomas.
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PMID:Bcl-2 and Bcl-X expression in gangliogliomas. 1037 80

Vitronectin (VN) is an extracellular matrix (ECM) protein, the synthesis of which in vivo by glioma cells correlates with tumor grade. Although the role of VN as a permissive substrate for glioma migration has been well characterized, its role in conferring a survival advantage for tumor cells has not been addressed previously. By using an in vitro assay of DNA fragmentation as a quantitative measure of apoptotic cell death, we sought to determine whether the sensitivity of two human glioma cell lines (D54 and U251) to drug-induced apoptosis could be inhibited by VN. As well, the extent to which apoptosis could be inhibited was correlated with the levels of the Bcl-2 family of proteins that are known to modulate apoptosis and chemoresistance. Results of the study were: (a) VN coatings, in a dose-dependent manner, inhibited topoisomerase (Topo)-induced apoptosis by up to 50% (optimal coating density, 500 ng/cm2); in contrast, fibronectin (FN), an ECM protein present in abundance in the brain, demonstrated no protection; (b) in a dose-response study, VN clearly conferred a survival advantage (LD50 of Topo: on VN, 120 ng/ml; on FN, 35 ng/ml); (c) the protective effect of VN was not due to enhanced cell adhesion or alterations in the cell cycle distribution; (d) both of the classic integrin receptors that bind VN (alpha(v)beta3, alpha(v)beta5) were capable of mediating this protective effect, because ligation of either of the two classic integrins conferred chemoresistance to Topo; and (e) chemoresistance observed with VN was associated with an increase in expression of two antiapoptotic proteins, Bcl-2 and Bcl-X(L), with a consequent increase in the ratios for Bcl-2:Bax and Bcl-X(L):Bax. VN, an ECM protein preferentially expressed at the tumor-brain interface in vivo, may confer a survival advantage to glioma cells at the advancing tumor margin and may thus, in part, underlie the high level of tumor recurrence at this interface.
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PMID:Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. 1038 48

Gliomas express a higher amount of Fas than normal brain tissue. It is of interest to know whether expression of the Fas receptor is unfavorable to the antiapoptotic pathways in gliomas. In this study, we introduced the Fas gene via an adenovirus vector (Adeno-Fas) into the A-172, U251, and U-373 MG glioma cell lines, each of which expresses Fas on the cell surface. Infection of Adeno-Fas induced apoptosis in each glioma cell line. In U251 cells and A-172 cells that express the same level of Fas as a result of infection with Adeno-Fas, a much higher percentage of U251 cells underwent apoptosis than did A-172 cells. This suggests that each glioma cell line has its own threshold of Fas expression, above which apoptosis is induced, and that the constitutive expression of Fas is below the level of this threshold. It was found that the constitutive expression of the anti-apoptotic gene Bcl-X(L) is higher in A-172 cells than in U251 cells. Adenovirus-mediated transduction of the Bcl-X(L) gene into U251 cells effectively suppressed Adeno-Fas-mediated apoptosis. These data indicate that the Bcl-X(L) gene is one of the important determinants of the threshold for Fas-mediated apoptosis. When U251 and U-373 MG cells were transduced with the Fas gene controlled by the myelin basic protein promoter, which had been shown to be active in gliomas but not in neural tissues, the cells underwent markedly enhanced apoptosis. Taken together, these results indicate that the overexpression of Fas alone induced apoptosis in each glioma cell line. The degree of Fas-mediated apoptosis was attenuated by the expression of an anti-apoptotic gene, Bcl-X(L). The adenovirus-mediated induction of Fas gene controlled by a tissue-specific promoter (e.g., myelin basic protein promoter) would be a promising therapeutic approach for malignant glioma.
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PMID:Adenovirus-mediated overexpression of Fas induces apoptosis of gliomas. 1077 Jun 30

Exposure to 1,3-dinitrobenzene (DNB) is associated with neuropathologic changes in specific brainstem nuclei, mediated by oxidative stress and mitochondrial dysfunction. The expression of Bcl-2-family proteins as a function of sensitivity to 1, 3-dinitrobenzene (DNB)-induced mitochondrial permeability transition (MPT) was examined in C6 glioma and SY5Y neuroblastoma cells. Neuroblastoma cells were 10-fold more sensitive than glioma cells to DNB-induced decreases in mitochondrial reducing potential, measured by reduction of the tetrazolium compound, 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT). The IC(50) values for DNB-related inhibition of MTT reduction were 107+/-25 microM in SY5Y cells and 1047+/-101 microM in C6 cells. Levels of reactive oxygen species (ROS) were increased in both SY5Y and C6 cells following DNB exposure by 4.6- and 6.0-fold above control, respectively. DNB caused abrupt depolarization of mitochondria in both neuroblastoma and glioma cells that was inhibited by trifluoperazine. The first order rate constants for mitochondrial depolarization were: C6, k=0.31+/-0.02 min(-1); SY5Y, k=0.14+/-0.01 min(-1). Onset of MPT occurred at 10-fold lower concentration of DNB in SY5Y cells than in C6 cells. The antioxidants, deferoxamine and alpha-tocopherol, effectively prevented DNB-induced MPT in C6 and SY5Y cells, suggesting involvement of ROS in the initiation of MPT. Exposure to DNB resulted in decreased cellular ATP content in SY5Y cells and efflux of mitochondrial calcium in both SY5Y and C6 cells, concurrent with onset of MPT. The expression of Bcl-2, Bcl-X(L), and Bax was evaluated in both cell types by Western blot analysis. C6 glioma cells strongly expressed Bcl-X(L) and only weakly expressed Bcl-2 and Bax, whereas SY5Y neuroblastoma cells expressed lower levels of Bcl-X(L) and higher levels of both Bcl-2 and Bax. Collectively, these results suggest that higher constitutive expression of Bcl-X(L), rather than Bcl-2, correlates with resistance to DNB-induced MPT in SY5Y and C6 cells and that differential regulation of the permeability transition pore may underlie the cell-specific neurotoxicity of DNB.
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PMID:Differential cellular regulation of the mitochondrial permeability transition in an in vitro model of 1,3-dinitrobenzene-induced encephalopathy. 1096 Jun 1

Several apoptosis-related genes have been reported to be involved in chemotherapy-induced apoptosis in cancers. An assessment of the relationship between expression of those genes and the degree of chemotherapy-induced apoptosis may be useful in improving the efficacy of cancer therapy. We transduced Apaf-1 (apoptotic protease-activating factor-1) and caspase-9 into U-373MG glioma cells using adenovirus (Adv) vectors in the presence of etoposide and evaluated the degree of apoptosis. The degree of apoptosis in etoposide-treated U-373MG cells infected with Adv for Apaf-1 (Adv-APAF1) was higher (27%) than that in cells infected with control Adv (14%), that in cells infected with Adv for caspase-9 (Adv-Casp9) was higher (34%) than that in cells infected with Adv-APAF1, and that in cells infected with both Adv-APAF1 and Adv-Casp9 was the highest (41%). Treatment with etoposide increased expression of p53 and decreased expression of Bcl-X(L) in U-373MG cells which harbored mutant p53. These results indicate that the expression of Apaf-1 and caspase-9 may be important determinants in predicting the sensitivity of cancers to chemotherapy. Adv-mediated co-transduction of Apaf-1 and caspase-9 should render cancer cells highly sensitive to chemotherapy.
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PMID:Co-transduction of Apaf-1 and caspase-9 augments etoposide-induced apoptosis in U-373MG glioma cells. 1134 70

APRIL (a proliferation-inducing ligand) is a newly identified member of the tumor necrosis factor (TNF) family. Tumor growth-promoting as well as apoptosis-inducing effects of APRIL have been described. Here, we report that five of 12 human malignant glioma cell lines express APRIL. APRIL gene transfer experiments revealed that malignant glioma cells are refractory to growth-promoting activity of APRIL in vitro and in vivo. Interestingly, ectopic expression of APRIL confers minor protection from apoptotic cell death induced by the death ligands, CD95 ligand (CD95L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand (Apo2L). This antiapoptotic activity is specific for death ligand/receptor-mediated apoptosis since APRIL does not protect glioma cells from the cytotoxicity of the drugs, teniposide, vincristine, lomustine or cisplatin. Ectopic expression of APRIL is associated with the upregulation of X-linked inhibitor of apoptosis protein (XIAP), providing a possible explanation for the antiapoptotic activity observed here. In contrast, APRIL does not regulate the expression levels of the antiapoptotic proteins FLICE-inhibitory protein (FLIP), Bcl-2 or Bcl-X(L). These findings suggest that APRIL is involved in the regulation of death ligand-induced apoptotic signaling in malignant glioma cells.
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PMID:APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis. 1155 92

Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6-24 h after administration both in vivo and in vitro. This effect was critically dependent on p53 and caspase-9 expression. The long-term effect of intrauterine ENU exposure was examined in control and p53-deficient mice. High grade glial tumors were found in 60% of p53(-/-) young adult mice exposed to ENU on gestational day 12.5 but not in p53(+/-) or p53(+/+) littermates or in untreated p53-deficient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial fibrillary acidic protein and the anti-apoptotic molecule Bcl-X(L). These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with specific genetic abnormalities (e.g. p53 deficiency) to produce glial neoplasms in the adult brain.
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PMID:Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure. 1178 43

Bad, a proapoptotic member of the Bcl-2 family, is inactivated by phosphorylation, and this loss of activity may contribute to the malignancy of certain types of tumors such as glioblastoma and prostate cancer. To determine whether extracellular Bad can be delivered into cells via cell surface receptor binding and induce apoptosis, we genetically fused the mouse Bad gene to the gene for the translocation and receptor-binding domains of diphtheria toxin (DTTR). The purified Bad (wild-type)-DTTR protein showed cytotoxicity to human glioma cells in a dose-dependent manner. Bad phosphorylation sites at codons 112 and 136 were mutated from serine to alanine to prevent Bad inactivation by kinases and to increase the toxicity of Bad. The Bad (S112A S136A)-DTTR protein was at least 5 times more toxic than Bad (wild-type)-DTTR with an IC(50) of 5 x 10(-8) M. The Bad (S112A S136A)-DTTR protein altered the subcellular distribution of Bcl-X(L), indicating that it enters the cell cytoplasm and binds Bcl-X(L). Bad (S112D S136A)-DTTR, mutated to mimic phosphorylation of Bad, showed lower toxicity than either Bad (wild-type)-DTTR or Bad (S112A S136A)-DTTR, additionally indicating that Bad-DTTR must bind Bcl-X(L) to stimulate apoptosis. We conclude that extracellular Bad can be delivered into cells via the transport domain of a bacterial toxin and may be used to induce apoptosis.
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PMID:Extracellular Bad fused to toxin transport domains induces apoptosis. 1188 16

Temozolomide (TMZ) is a newly approved alkylating agent for the treatment of malignant gliomas. To investigate resistance mechanisms in a multidrug therapeutic approach, a TMZ-resistant human glioma cell line, SF188/TR, was established by stepwise exposure of human SF188 parental cells to TMZ for approximately 6 months. SF188/TR showed 6-fold resistance to TMZ and cross-resistance to a broad spectrum of other anticancer agents that included 3-5-fold resistance to melphalan (MEL), gemcitabine (GEM), paclitaxel (PAC), methotrexate (MTX), and doxorubicin (DOX), and 1.6-2-fold resistance to cisplatin (CDDP) and topotecan (TPT). Alkylguanine alkyltransferase (AGT) activity was increased significantly in the resistant cell line compared with the parental cell line (P<0.05), whereas no significant differences occurred in the cellular uptake of TMZ and PAC between resistant and parental cells. Depletion of AGT by O(6)-benzylguanine significantly increased the cytotoxicity of TMZ in both the sensitive and resistant cell lines, but did not influence the cytotoxicity of the other drugs tested. Treatment with TMZ caused SF188 cells to accumulate in S phase, whereas SF188/TR cells were unaffected. Expression of Bcl-2 family members in SF188/TR cells compared with SF188 cells indicated that the pro-apoptotic proteins (i.e. Bad, Bax, Bcl-X(S)) were reduced 2-4-fold in the resistant cell line, whereas the anti-apoptotic proteins Bcl-2 and Bcl-X(L) were expressed at similar levels in both cell lines. In conclusion, the mechanism of resistance of SF188/TR cells to TMZ involved increased activity of AGT, a primary resistance mechanism, whereas the broad cross-resistance pattern to other anticancer drugs was due to a common secondary resistance mechanism related to alterations in the relative expression of the pro-apoptotic and anti-apoptotic proteins.
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PMID:Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. 1196 May 98

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