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

Apoptosis of glioma may represent a promising intervention for tumor treatment. Macrophages are able to induce apoptosis in a number of tumor cells, including glioma. It is known that apoptosis of cells is executed on either a death receptor-dependent or independent pathway. Whether and how apoptosis of glioma cells induced by activated macrophages is involved in these two pathways simultaneously are not known. Using in vitro and in vivo experimental models, we investigated Bcl-2 system and Fas/FasL channel, representing the death receptor-dependent and independent pathways, respectively, in glioma cells treated with the supernatant from the activated macrophages, which was rich in tumor necrosis factor-alpha and interferon-gamma. We found that levels of Fas and FasL were up-regulated both in vitro and in vivo, accompanying an increase in the expression of caspase-8. The number of apoptotic cells was also increased significantly, although the percentage of death cells exceeded the number of tumor cells positive for Fas or FasL. It was also evident that the expression of Bax was increased, whereas the level of Bcl-2 was decreased, in glioma cells treated with the supernatant from the activated macrophages. The alteration of molecules related to both death pathways led to apoptosis of glioma and the inhibition of xenograft glioma growth in mice. Apoptosis of glioma induced by the activated macrophage is executed by way of both death receptor-dependent and independent pathways, and such an apoptosis-induced approach can effectively inhibit the growth of glioma in vivo.
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PMID:Glioma apoptosis induced by macrophages involves both death receptor-dependent and independent pathways. 1262

Preclinical studies in animal models and human clinical trials have evaluated the safety and efficacy of adenoviral vectors for cancer gene therapy. These studies have indicated that gene delivery via adenoviral vectors, including p53 gene therapy, represents a promising therapeutic modality for many types of human cancers. This review focuses on novel strategies to induce apoptosis in glioma cells by transduction with adenoviral vectors carrying a variety of apoptosis-related genes, including Fas ligand, Fas, FADD, caspase-8, p53, p33ING1, p73alpha, Bax, Apaf-1, caspase-9, IkappaBdN, caspase-3, Bcl-2, and Bcl-X(L). We conclude that adenoviral vector-mediated delivery of apoptosis-related genes other than p53 is a potentially useful gene therapy approach toward the treatment of human brain tumors.
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PMID:Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells. 1265 7

Glioblastoma is a lethal neoplasm resistant to conventional radiotherapy and chemotherapy. Natural born killer (NBK), also known as Bcl-2-interacting killer (BIK), is a death-promoting Bcl-2 family protein sharing with Bcl-2 only the Bcl homology 3 (BH3) domain. We here report that an adenoviral vector encoding NBK (Ad-NBK) uniformly induces cell death in 12 human malignant glioma cell lines. Ad-NBK-induced cell death involves neither quantitative mitochondrial cytochrome c release nor caspase 8, 9, 7, or 3 processing and is unaffected by the viral caspase inhibitor, cytokine response modifier A (CRM-A), or selective caspase 8 or 9 inhibitors. In contrast, Ad-NBK-induced cell death is inhibited by the broad-range caspase inhibitor, zVAD-fmk, or by adenoviral gene transfer of the X-linked inhibitor of apoptosis protein (XIAP). Further, Ad-NBK-induced cell death is inhibited by Bcl-2 or Bcl-xL gene transfer. Interestingly, Bcl-2- and Bcl-xL-transfected glioma cells, which are partially protected from Ad-NBK-induced cell death, accumulate much higher levels of NBK than are ever observed in control-infected cells. This indicates that complex formation with Bcl-2 or Bcl-xL sequesters NBK in an inactive form and that free NBK, rather than an NBK-mediated depletion of free antiapoptotic Bcl-2 family proteins, is the proximate mediator of Ad-NBK-induced cell death. Conversely, proteasome inhibition-mediated accumulation of NBK strongly enhances Ad-NBK-induced cell death. Finally, Ad-NBK-infected LN-229 glioma cells are not tumorigenic in nude mice. Thus Ad-NBK triggers an XIAP- and zVAD-fmk-sensitive cell death pathway in glioma cells with potential therapeutic value, provided that NBK expression can be selectively targeted to cancer cells.
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PMID:Adenoviral natural born killer gene therapy for malignant glioma. 1295 95

Many malignant glioma cells express death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL-induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase-8-initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild-type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to downregulate caspase-8 inhibitor c-FLIP(S) (the short form of cellular Fas-associated death domain-fike interleukin-1-converting enzyme-inhibitory protein) and up-regulate Bak, a pro-apoptotic Bcl-2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.
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PMID:TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways. 1465 59

Adenoviral p53 gene transfer (Ad-p53) induces apoptosis in glioma cells expressing mutant p53, but fails in cells with wild-type p53. Endogenously, gliomas express varied levels of Fas/CD95, yet constitutively high levels of Fas/CD95 ligand. Because the mechanism behind the differential apoptotic response to Ad-p53 infection remains elusive, we examined how the Fas/CD95 pathway is involved in U87MG (wt-p53), D54 (wt-p53), U251MG (mutant-p53), and U373MG (mutant-p53) glioma cell lines. Ad-p53 infection did not alter the levels of Fas/CD95 ligand in either wild-type or mutant p53-expressing cell lines. In contrast, Ad-p53 infection led to an approximately 3-fold increase in Fas/CD95 mRNA expression in mutant p53-bearing cell lines but not in their wild-type (wt) counterparts, as assessed in an RNase protection assay. Fas/CD95 mRNA induction appeared to be regulated at the transcriptional level because Ad-p53 infection resulted in up to a 4-fold increase in Fas/CD95 promoter reporter activity. Subsequently, flow cytometric analysis revealed a 2- to 4-fold increase in surface Fas/CD95 expression following Ad-p53 infection in mutant-p53-containing cell lines. Use of the protein transport inhibitor Brefeldin A significantly inhibited Ad-p53-induced surface Fas/CD95 expression, but only partially inhibited apoptosis in mutant-p53 cell lines. These results suggest that p53 regulates Fas/CD95 expression at the transcriptional level and through protein trafficking in mutant-p53 cell lines. Fluorogenic activity assays demonstrated that induction of caspase-8 activity following Ad-p53 infection correlated with increases in Fas/CD95 expression. Incubating cells with a caspase-8-specific inhibitor Ac-IETD-CHO prior to Ad-p53 infection inhibited caspase-8 activity and apoptosis. Together, our results suggest that regulation of the Fas/CD95 pathway is partly responsible for Ad-p53-induced apoptosis in glioma cells, which depends on the p53 status of the involved cells. Additionally, the inability of Ad-p53 to activate the Fas/CD95 pathway in wt-p53 glioma cells coincides with their apoptotic-resistant phenotype. Further elucidation of the nature of this resistance could ultimately augment the efficacy of Ad-p53 gene therapy.
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PMID:Differential activation of the Fas/CD95 pathway by Ad-p53 in human gliomas. 1471 18

Specific activation of apoptosis in tumor cells offers a promising approach for cancer therapy. Induction of apoptosis leads to activation of specific proteases. Two major pathways for caspase activation in mammalian cells have been described. One apoptotic pathway involves members of the tumor necrosis factor family of cytokine receptors (eg death receptor 5 (DR5)). The other pathway is controlled by the Bcl-2 family of proteins. The purpose of this study was to investigate whether increased apoptosis occurs in human glioma cells following infection with a recombinant adenoviral vector encoding the human Bax gene under the control of human vascular endothelial growth factor (VEGF) promoter element (AdVEGFBax) in combination with an anti-human DR5 monoclonal antibody (TRA-8). Specific overexpression of exogenous Bax protein induced apoptosis and cell death in glioma cell lines, through activation of both caspase-8 and -9, leading to activation of downstream caspase-3. The relative sensitivity to AdVEGFBax for the glioma cell lines was U251MG>U373MG>U87MG>D54MG. The recently characterized TRA-8 monoclonal antibody induces apoptosis of most TRAIL-sensitive tumor cells by specific binding to DR5 receptors on the cellular membrane. TRA-8 induced rapid apoptosis and cell death in glioma cells, but did not demonstrate detectable cytotoxicity of primary normal human astrocytes. The efficiency of TRA-8-induced apoptosis was variable in different glioma cell lines. The relative sensitivity to TRA-8 was U373MG>U87MG>U251MG>D54MG. The combination of TRA-8 treatment and overexpression of Bax overcame TRA-8 resistance of glioma cells in vitro. Cell viability of U251MG cells was 71.1% for TRA-8 (100 ng/ml) alone, 75.9% for AdVEGFBax (5 MOI) alone and 41.1% for their combination as measured by MTS assay. Similar enhanced apoptosis results were obtained for the other glioma cell lines. In vivo studies demonstrated that the combined treatment significantly (P<0.05) suppressed the growth of U251MG xenografts and produced 60% complete tumor regressions without recurrence. These data suggest that the combination of TRA-8 treatment with specific overexpression of Bax using AdVEGFBax may be an effective approach for the treatment of human malignant gliomas.
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PMID:Enhanced apoptosis following treatment with TRA-8 anti-human DR5 monoclonal antibody and overexpression of exogenous Bax in human glioma cells. 1497 47

Fifty percent of high-grade glioma patients die within a year of diagnosis and less than two percent survive five years postdiagnosis. Elucidating apoptosis signaling pathways may assist in designing better adjuvant therapies. Preliminary characterizations suggested that glioma cells may either employ mitochondrial-independent or -dependent death receptor-induced apoptotic pathways, characteristic of cells termed type I and type II, respectively. In the present study, we generated panels of clonal transfectants overexpressing various levels of Bcl-2, in two parental glioma cell lines. These cells were used to explore molecular factors determining the necessity for mitochondrial amplification of death receptor signaling. Moderate Bcl-2 expression was sufficient to render one glioma cell line (D270) resistant to apoptosis induced by Fas ligand or TRAIL, consistent with these cells being type II. However, expression of even very high levels of Bcl-2 in a second line (D645) did not affect death ligand sensitivity, indicative of a type I phenotype. D270 cells expressed much less caspase-8 protein than D645 cells. Enforced overexpression of caspase-8 (or cytoplasmic Diablo/Smac) in D270 cells overcame Bcl-2 inhibition of death ligand-induced apoptosis, converting them from type II to type I. This indicates that caspase-8 levels can influence the requirement for mitochondrial involvement in death receptor apoptotic signaling in glioma cells.
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PMID:Caspase-8 levels affect necessity for mitochondrial amplification in death ligand-induced glioma cell apoptosis. 1499 47

The detailed mechanisms behind the resistance of malignant gliomas to therapy are not known. Inherent resistance to apoptosis is, however, one plausible explanation. In the present study we tried to delineate the molecular defects and to induce apoptosis by inducible caspases in three apparently apoptosis resistant glioma cell lines. U-105 MG, U-251 MG, and SF-767 were resistant to Fas-induced apoptosis as shown by the lack of Fas-induced cell death, morphological changes, annexin-V reactivity, Parp cleavage, caspase-3 cleavage, and caspase-3 activation. The glioma cells showed no consistent down-regulation of the pro-apoptotic proteins Fas, Fadd, caspase-3, caspase-8, caspase-9, Apaf-1, Bid, Bad, or Bax, and no consistent up-regulation of the anti-apoptotic proteins Bcl-x or Bcl-2. In U-105 MG, Fas was, however, not detected at the cell surface indicating intracellular retention. To assess if the apoptotic blocks could be by-passed, we introduced the so-called artificial death switches, i.e., inducible caspases and Fadd, into the glioma cells. Synthetic activation of inducible caspase-3, but not of caspase-8, resulted in apoptosis in the three glioma cell lines and inducible Fadd induced apoptosis in SF-767. The results were consistent with a block in the apoptotic signaling pathways of glioma cells between caspase-8 and caspase-3 activation, and that inducible Fadd could induce caspase-8 independent apoptosis in some cells. Apparently resistant glioma cells could thus be induced to undergo apoptosis by activation of appropriate death switches. This might have implications for the design of future therapeutic strategies.
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PMID:Induction of apoptosis in resistant glioma cells by synthetic caspase-activation. 1501 72

Previously, we evaluated the therapeutic efficacy of the adenovirus-mediated transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for malignant gliomas. However, the molecular pathways that mediate the 5-FC/CD gene therapy-induced cell death remains to be elucidated. In this study, we examined the induction of apoptosis and the role of caspases in 5-FC/CD gene therapy using human malignant glioma cells [Gli36delta5 (mutated p53) and U87MG (wild p53)]. The treatment with 5-FC/CD gene-therapy-induced apoptosis both in Gli36delta5 cells and in U87MG cells according to flow cytometric analysis. Immunoblot analysis revealed that caspases 3 and 9 were processed in response to 5-FC/CD in a concentration- and time-dependent manner, but caspase 8 was not. Each caspase 3 and 9 inhibitor significantly reduced apoptosis triggered by 5-FC/CD, but the caspase 8 inhibitor did not affect apoptosis induction. 5-FC/CD significantly promoted the release of cytochorme c from mitochondria in a concentration-dependent manner. These results indicate that 5-FC/CD gene therapy induces apoptosis in human malignant glioma cells and that the apoptotic cell death is mediated by the activation of mitochondrial caspase cascades involving caspases 3 and 9. This is the first report concerning the apoptotic mechanism of 5-FC/CD gene therapy, and these findings could be used to increase the efficacy of suicide gene therapy systems for the treatment of malignant glioma.
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PMID:Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus. 1501 77

The present study was designed to examine the roles of p53, reactive oxygen species (ROS), and ceramide, and to determine their mutual relationships during tumor necrosis factor (TNF)-alpha-induced apoptosis of human glioma cells. In cells possessing wild-type p53, TNF-alpha stimulated ceramide formation via the activation of both neutral and acid sphingomyelinases (SMases), accompanied by superoxide anion (O2-*) production, and induced mitochondrial depolarization and cytochrome c release, whereas p53-deficient cells were partially resistant to TNF-alpha and lacked O2-* generation and neutral SMase activation. Restoration of functional p53 sensitized glioma cells expressing mutant p53 to TNF-alpha by accumulation of O2-*. z-IETD-fmk (benzyloxycarbonyl-Ile-Glu-Thr-Asp fluoromethyl ketone), but not z-DEVD-fmk (benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethyl ketone), blocked TNF-alpha-induced ceramide formation through both SMases as well as O2-* generation. Caspase-8 was processed by TNF-alpha regardless of p53 status of cells or the presence of antioxidants. Two separate signaling cascades, p53-mediated ROS-dependent and -independent pathways, both of which are initiated by caspase-8 activation, thus contribute to ceramide formation in TNF-alpha-induced apoptosis of human glioma cells.
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PMID:Molecular mechanisms of TNF-alpha-induced ceramide formation in human glioma cells: P53-mediated oxidant stress-dependent and -independent pathways. 1513 91


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