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)

Interferon-gamma (IFN-gamma) modulates the expression of Class II major histocompatibility antigens (MHC), thus providing a potential regulatory mechanism for local immune reactivity in the context of MHC-restricted antigen presentation. Within the central nervous system (CNS), the expression of MHC Class II antigens has been demonstrated on human reactive astrocytes and glioma cells. In order to investigate the modulation of HLA-DR on normal astrocytes, two cell lines were grown from a 20-week-old fetal brain. In situ none of the fetal brain cells expressed HLA-DR as determined by immunohistology on frozen tissue sections. The two cell lines, FB I and FB II, expressed GFAP indicating their astrocytic origin. FB I was HLA-DR negative at the first tissue culture passages, but could be induced to express HLA-DR when treated with 500 U/ml IFN-gamma. FB II was spontaneously HLA-DR positive in the early passages, lost the expression of this antigen after 11 passages and could also be induced to express HLA-DR by IFN-gamma. The induction of HLA-DR expression was demonstrated both by a binding RIA and by immunoprecipitation using a monoclonal antibody (MAB) directed against a monomorphic determinant of HLA-DR. The HLA-DR alloantigens were determined on FB II cells after IFN-gamma treatment, by immunofluorescence and by cytotoxicity assays, and were shown to be DR4, DR6, Drw52, DRw53 and DQwl. These results show that human fetal astrocytes can be induced to express HLA-DR by IFN-gamma in vitro and support the concept that astrocytes may function as antigen-presenting cells.
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PMID:Cultured human fetal astrocytes can be induced by interferon-gamma to express HLA-DR. 310 54

APO2L (TRAIL) is a novel CD95L (Fas/APO-1-L) homologous cytotoxic cytokine that interacts with various receptors which transmit (DR4, DR5) or inhibit (DcR1, DcR2) an apoptotic signal. Here, we report that human glioma cell lines preferentially express mRNAs for agonistic death receptors DR4 (8/12) and DR5 (11/12) rather than the death-inhibitory decoy receptors DcR1 (4/12) and DcR2 (2/12). Ten of 12 cell lines are susceptible to APO2L-induced apoptosis. The resistant cell lines, U138MG and U373MG, are cross-resistant to CD95L-induced apoptosis. Similar to CD95L-induced apoptosis, APO2L-induced apoptosis is inhibited by ectopic expression of the caspase inhibitor, crm-A, or of bcl-2, or by coexposure to the corticosteroid, dexamethasone, or the lipoxygenase inhibitor, nordihydroguaretic acid. There is no correlation between p53 genetic status of the cell lines and their susceptibility to APO2L-induced apoptosis, but the latter is moderately enhanced by ectopic expression of wild-type p53. APO2L targeting may be a promising approach for selectively targeting apoptosis to human malignant glioma cells.
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PMID:APO2 ligand: a novel lethal weapon against malignant glioma? 961 12

AP02 ligand (APO2L) is a CD95 ligand (CD95L)-related cytokine of the tumor necrosis factor family that interacts with agonistic (DR4, DR5) and antagonistic (DcR1, DcR2) receptors. Cultured malignant glioma cells preferentially express agonistic receptors and are susceptible to APO2L-induced apoptosis. Here, we report that 8 of 8 human glioma cell lines expressed APO2L mRNA and protein in vitro. Immunohistochemistry using a monoclonal antibody to APO2L revealed that all 23 primary astrocytic brain tumors analyzed, including low-grade astrocytomas and glioblastomas, express APO2L in vivo. With the exception of reactive astrocytes, non-neoplastic glia and neurons in the cerebrum lacked immunoreactivity of APO2L. Thus, in addition to the CD95/CD95L system, a second death ligand/death receptor pair may regulate susceptibility to apoptosis in human glial neoplasms.
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PMID:Human astrocytic brain tumors express AP02L/TRAIL. 993 Aug 88

The intractability of malignant gliomas to multimodality treatments plays a large part in their extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel member of the tumor necrosis factor (TNF) family that induces apoptosis preferentially in tumor cells through binding to its cognate death receptors, DR4 and DR5. Here we show that the DNA-damaging chemotherapeutic drugs, cis-diamminedichloroplatinum(II) (CDDP) and etoposide, elicited increased expression of DR5 in human glioma cells. Exposure of such cells in vitro to soluble human TRAIL in combination with CDDP or etoposide resulted in synergistic cell death that could be blocked by soluble TRAIL-neutralizing DR5-Fc or the caspase inhibitors, Z-Asp-CH2-DCB and CrmA. Moreover, systemic in vivo administration of TRAIL with CDDP synergistically suppressed both tumor formation and growth of established s.c. human glioblastoma xenografts in nude mice by inducing apoptosis without causing significant general toxicity. The combination treatment resulted in complete and durable remission in 29% of mice with the established s.c. xenografts and also significantly extended the survival of mice bearing intracerebral xenografts. These results provide preclinical proof-of-principle for a novel therapeutic strategy in which the death ligand, TRAIL, is safely combined with conventional DNA-damaging chemotherapy.
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PMID:Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. 1070 92

TRAIL/Apo-2L, a novel cytokine, is a member of the tumor necrosis factor (TNF) family and serves as an extracellular signal triggering apoptosis. TRAIL/Apo-2L is capable of killing various transformed cells but not unstimulated primary T cells. In this study, five human glioma cells (U87, U118, U178, U563, and A172) were examined for their susceptibility to the apoptotic effects of TRAIL/Apo-2L. TRAIL/Apo-2L cDNA was isolated by RT-PCR, and recombinant TRAIL/Apo-2L protein was purified by the pMAL-c2 system (New England Biolabs, Beverly, MA). Exposure of A172 cells to bacterially expressed soluble TRAIL/Apo-2L fusion protein at a concentration of 1 microg/ml resulted in significant cell death over a 24-h period. Three experiments were performed to suggest that the TRAIL/Apo-2L killing was through the induction of apoptosis of A172 target cells. In addition, the expression of TRAIL/Apo-2L in different glioma cells was found to be variable, and TRAIL/Apo-2L-induced apoptosis was in a cell type-dependent manner. Some correlation between the susceptibility to TRAIL/Apo-2L and the expression level of one of its cognate receptors, DR4, was observed. In addition, cycloheximide worked synergistically with TRAIL/Apo-2L to induce apoptosis in glioma cells.
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PMID:Induction of apoptosis in glioma cell lines by TRAIL/Apo-2l. 1093 34

Apo2 ligand tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of the tumor necrosis factor family that interacts with cell surface "death receptors" (DR4 and DR5) to initiate programmed cell death. Apo2L/TRAIL also binds to "decoy" receptors (DcR1 and DcR2) that can antagonize its interaction with DR4 and DR5. In recent studies, Apo2L/TRAIL has been noted to produce selective toxicity toward certain neoplastic cells versus normal cells. The decoy receptors may in part contribute to this selectivity, because they are expressed in various normal tissues but are present at low or undetectable levels in certain types of neoplastic cells. In the current study, we examined the potential therapeutic applicability of recombinant soluble Apo2L/TRAIL by investigating its effects in vitro and in vivo against a series of cell lines derived from malignant gliomas, which are often resistant to conventional treatment modalities. In cell proliferation assays, Apo2L/TRAIL produced a striking decrease in cell numbers, with a median inhibitory concentration of 30-100 ng/ml, in the TP53 wild-type high-grade glioma cell lines U87 and A172, the TP53-mutated T98G, and the TP53-deleted LN-Z308. In contrast, no significant effects were observed in non-neoplastic astrocytes at concentrations up to 3000 ng/ml. Clonogenic assays showed that exposure to Apo2L produced a time-dependent decrease in the viability of glioma-derived cell lines. This correlated with the induction of apoptosis as assessed by a terminal transferase-catalyzed in situ end-labeling assay. Pretreatment of the cells with the caspase inhibitors Acetyl-Asp-Glu-Val-L-aspartic acid aldehyde or Acetyl-Tyr-Val-Ala-Asp-chlormethylketone (200 microM) largely eliminated the effects of Apo2L/TRAIL. Administration of Apo2L/TRAIL (0.3, 1, 3, 10, and 30 mg/kg/day for 7 days via i.p. infusion) to nude mice harboring established intracranial U87 xenografts produced a significant, dose-dependent prolongation of survival versus control animals. Survival in the control group was 27 +/- 1.7 days, compared with more than 50 days in each of the treatment groups (P < 0.001). At the 30 mg/kg dose level, 100% of animals survived for 120 days without evidence of tumor, a substantial improvement in comparison with lower dose levels (P < 0.01). No overt toxicity was apparent even at the highest Apo2L dose. We conclude that soluble Apo2L/TRAIL is effective in inducing apoptosis in high-grade glioma cells in vitro. Because this ligand appears to exhibit selective cytotoxicity for glioma cells versus non-neoplastic cells in vitro and demonstrates significant activity in vivo when administered systemically in an otherwise uniformly fatal central nervous system glioma model system, Apo2L may constitute a useful therapeutic agent for these challenging tumors.
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PMID:Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. 1135 Sep 7

Death ligands such as CD95 ligand (CD95L) or tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) induce apoptosis in radiochemotherapy-resistant human malignant glioma cell lines. The death-signaling TRAIL receptors 2 (TRAIL-R2/death receptor (DR) 5) and TRAIL-R1/DR4 were expressed more abundantly than the non-death-inducing (decoy) receptors TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in 12 human glioma cell lines. Four of the 12 cell lines were TRAIL/Apo2L-sensitive in the absence of a protein synthesis inhibitor, cycloheximide (CHX). Three of the 12 cell lines were still TRAIL/Apo2L-resistant in the presence of CHX. TRAIL-R2 expression predicted sensitivity to apoptosis. Coexposure to TRAIL/Apo2L and cytotoxic drugs such as topotecan, lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU) or temozolomide resulted in synergistic killing. Synergistic killing was more often observed in cell lines retaining wild-type p53 activity (U87MG, LN-229) than in p53 mutant cell lines (LN-18, T98G, U373MG). Drug exposure resulted in enhanced TRAIL-R2 expression, but decreased TRAIL-R4 expression in U87MG cells. Ectopic expression of dominant-negative p53(V135A) abrogated the drug-induced changes in TRAIL-R2 and TRAIL-R4 expression, but had no effect on synergy. Thus, neither wild-type p53 function nor changes in TRAIL receptor expression were required for synergy. In contrast, synergy resulted possibly from drug-induced cytochrome c release from mitochondria, serving as an amplifier of the TRAIL/Apo2L-mediated cascade of caspase activation. These data provide novel insights into the role of the TRAIL/Apo2L system in malignant gliomas and illustrate that TRAIL/Apo2L-based immunochemotherapy may be an effective therapeutic strategy for these lethal neoplasms.
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PMID:CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. 1146 79

The survival of patients with malignant gliomas is still unsatisfactory despite multimodality treatment, therefore new therapeutic strategies are required. Tumor necrosis factor apoptosis related ligand (TRAIL/Apo2L), a member of the tumor necrosis factor superfamily, may induce apoptotic cell death in several tumors, but not in normal cells, upon binding with specific receptors. In the present study, the expression and function of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) has been investigated in five human glioma cell lines (U87, U138, U373, A172, SW1783) in ex vivo tumors and in primary cultures obtained from the tumors. Our data show that gliomas preferentially express TRAIL R2 and that treatment with topotecan, a topoisomerase I inhibitor, significantly up-regulates its expression as detected by flow cytometry and western blotting. Moreover, in most cases, treatment with topotecan resulted in an increased sensitivity to TRAIL-dependent apoptosis, although cyclohexymide had to be added to induce apoptosis. On glioma cell lines, the effects of irradiation on TRAIL receptors were also analysed. In our experimental conditions, irradiation with 2 Gy had a modest additive effect on TRAIL-dependent apoptosis and was not able to modulate TRAIL receptor expression.
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PMID:In vitro effects of topotecan and ionizing radiation on TRAIL/Apo2L-mediated apoptosis in malignant glioma. 1571 69

The major aim of this study was to develop novel therapeutic approaches to potentiate and reactivate apoptosis induced by TNF-Related Apoptosis Inducing Ligand (TRAIL) in malignant glioma. Analysis of five glioma cell lines (U87, U251, U373, MZ-54 and MZ-18) indicated that only two of the cell lines were sensitive to apoptosis induced by TRAIL alone. TRAIL resistance was not correlated to expression levels of the death receptors DR4 and DR5 or the decoy receptors DcR1 and DcR2, suggesting that it was mediated by inactivation of TRAIL-induced downstream signalling. Activation of the BH3 only protein Bid and subsequent activation of the mitochondrial apoptosis pathway are known to play a pivotal role in TRAIL-induced apoptosis. Since this process is blocked by overexpression of anti-apoptotic Bcl-2 family members, we analyzed the therapeutic potential of BH3 mimetics in potentiating TRAIL-induced apoptosis. Treatment with TRAIL in combination with the specific Bcl-2 inhibitor HA14-1 and the Bcl-2/Bcl-xL inhibitor BH3I-2' potently enhanced apoptosis in TRAIL-sensitive U87 cells in a dose-dependent fashion. TRAIL-induced apoptosis was significantly reactivated by HA14-1 and BH3I-2' in one (U343) and two (MZ-54 and MZ-18) of three investigated TRAIL-insensitive cell lines, respectively. Knockdown of the anti-apoptotic Bcl-2 family member Mcl-1 by RNA interference had no additional effect on apoptosis induced by TRAIL and HA14-1 in U87 and U343 cells. Our data indicate that Bcl-2 and Bcl-xL play fundamental roles in TRAIL resistance of malignant glioma and suggest that using TRAIL or agonistic TRAIL receptor antibodies in combination with BH3 mimetics may represent a promising approach to reactivate apoptosis in therapy-resistant high grade gliomas.
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PMID:Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma. 1792 59

The treatment of malignant gliomas with current therapies remains a challenge in neurooncology. Our recent work showed that embryonic stem cell (ESC)-derived astrocytes conditionally expressing genes can be used to induce apoptosis in malignant glioma cells in vitro. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been shown to induce apoptosis in a variety of tumor cells, including gliomas. The aim of this study was to assess the proapoptotic effects of transgenic TRAIL delivered by ESC-derived astrocytes on malignant gliomas in vivo. Malignant glioma A172 cells were used to induce heterotopic xenografts in nude mice. ESC-derived astrocytes conditionally expressing TRAIL were injected into the xenografts. TRAIL expression was documented in the malignant glioma xenografts by reverse transcription PCR and immunohistochemistry after external gene induction. A significant reduction in tumor volume occurred 48 h after a single injection (14%) and double injections (31%) in the experimental groups. Terminal dUTP nick end labeling (TUNEL) revealed abundant apoptotic tumor cells in the experimental groups. Seven days after injection, the tumor had undergone severe necrosis, with only scattered residual tumor cells at the periphery. Death receptor DR4 expression increased significantly in the experimental groups compared with controls. Our data suggest that ESC-derived astrocytes conditionally expressing TRAIL should be considered as vectors to deliver gene therapy for malignant gliomas.
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PMID:In vivo gene delivery by embryonic-stem-cell-derived astrocytes for malignant gliomas. 1923 33


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