Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the course of human toxoplasmosis central nervous system involvement often occurs. As a model for toxoplasma growth within human brain cells the proliferation of Toxoplasma gondii strain BK within the human glioblastoma cell line 86HG39 was analysed. We found that 86HG39 cells support the growth of toxoplasma similar to human monocyte derived macrophages and in contrast to human monocytes. The growth of Toxoplasma gondii within interferon gamma (IFN gamma) treated 86HG39 cells is reduced due to toxoplasmostasis and not due to toxoplasmocide effects. The mechanism of IFN gamma induced toxoplasmostasis was also investigated. It was found that IFN gamma did not induce O2- production and/or nitrite oxide production, and inhibitors of O2- and NO2- did not influence IFN gamma induced toxoplasmostasis. In contrast, the supplementation of L-tryptophan to the culture medium completely abolished the IFN gamma effect. We therefore conclude that the induction of L-tryptophan degradation in 86HG39 cells by IFN gamma, possibly by activation of the indoleamine-2,3-dioxygenase, is responsible for the IFN gamma induced toxoplasmostasis within the glioblastoma cell line.
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PMID:Induction of toxoplasmostasis in a human glioblastoma by interferon gamma. 838 36

As part of continuing studies to investigate the possible regulatory effects of cytokines on malignant astrocytes, we investigated the effects of interleukin-4 (IL-4) alone and in combination with tumor necrosis factor-alpha (TNF alpha) and/or interferon-gamma (IFN gamma) on the cell growth and major histocompatibility complex (MHC) antigen expression of a cloned human glioblastoma cell line (9C). The 9C cells were treated with IL-4 alone or in combination with TNF alpha and/or IFN gamma and were examined for proliferation by crystal violet assay and for Class II MHC antigen by flow cytometry. Results indicated that IL-4 alone did not affect 9C proliferation. In combination with TNF alpha or IFN gamma, however, IL-4 significantly and dose-dependently inhibited cell growth. As previous reports have shown, TNF alpha combined with IFN gamma exerted an additive growth suppressive effect on glioblastoma cells, probably by enhancing TNF receptor expression. This additive effect of TNF alpha and IFN gamma was further enhanced by IL-4. In contrast, IL-4 did not modulate expression of Class II MHC antigen on 9C cells, even in combination with IFN gamma, which predictably enhanced this antigen. These results suggest that IL-4 is capable of modulating glioblastoma growth only in the presence of other cytokines, such as TNF alpha and/or IFN gamma. Further, the effect of IL-4 on glioblastoma proliferation is selective and independent of the mechanisms involved in regulating MHC antigen expression.
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PMID:Modulation of proliferation and antigen expression of a cloned human glioblastoma by interleukin-4 alone and in combination with tumor necrosis factor-alpha and/or interferon-gamma. 841 82

We have investigated the IFN-mediated inhibition of human parainfluenza virus-3 (HPIV-3) replication in cultured human A549 cells. IFN-alpha inhibited the virus yield significantly with concomitant reduction of viral RNA accumulation by more than 90%. Further studies indicated that the inhibitory action of IFN was at the level of primary transcription of HPIV3 replication. Since the IFN-inducible protein, MxA, has been shown to inhibit virus replication in several RNA viruses, we examined the role of MxA in HPIV-3 replication using a stably transfected human glioblastoma cell line expressing MxA. In these cells HPIV-3 replication was decreased by more than 100-fold depending on the virus dosage used with concomitant inhibition of viral RNA synthesis by about 80%. However, the viral primary transcription was not affected in this MxA-producing cell line. In contrast, in the parental cell line IFN-mediated inhibition occurred at the primary transcription step of HPIV-3 replication. These data suggest that in addition to MxA, other IFN-inducible proteins are involved in the anti-HPIV-3 effect of IFN in both the cell lines used.
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PMID:Inhibition of human parainfluenza virus-3 replication by interferon and human MxA. 866 84

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.
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PMID:Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma. 1130 15

Since malignant glioma displays moderate resistance to conventional therapy, a new treatment modality is needed to improve the outcome of patients with these tumors. In this study, we examined whether combination stimulation with interferon alpha (IFN-alpha) and retinoic acid (RA) affected proliferation of the glioblastoma cell line GB 12 in vitro. Stimulation with IFN-alpha alone inhibited the GB 12 cell proliferation in a dose/time-dependent fashion, as assessed by WST-1 assay and uptake of 3H-thymidine, while RA limited it only slightly. The anti-proliferative action of IFN-alpha against glioblastoma cells was enhanced by the addition of RA. The IFN-alpha/RA combination also induced apoptosis in a substantial portion of the cells, compared with either reagent alone. Bcl-2 family proteins, regulating apoptosis, were altered by these stimuli: Bcl-2 was down-regulated, while Bax-alpha was up-regulated, especially by the combination. These findings suggest that the IFN-alpha/RA combination would synergistically affect glioblastoma cell growth, probably through apoptosis induction as well as a decreased cellular DNA synthesis.
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PMID:Combined stimulation with interferon alpha and retinoic acid synergistically inhibits proliferation of the glioblastoma cell line GB12. 1239 8

Members of the ADAR (adenosine deaminases acting on RNA) gene family are involved in one type of RNA editing that converts adenosine residues to inosine. The A-to-I editing of serotonin receptor subtype 2C (5-HT(2C)R) mRNA leads to replacement of three amino acid residues located within the intracellular loop II domain, resulting in dramatic alterations in G-protein coupling functions of the receptor. It has been speculated that RNA editing may play a role in several pharmacological and behavioral processes where the serotonergic plasticity is mediated through 5-HT(2C)R. Interferon-alpha (IFN-alpha) often causes severe depression in patients treated for chronic viral hepatitis and certain malignancies. In this study, we examined the effects of IFN-alpha on RNA editing in human glioblastoma cell lines, which express 5-HT(2C)R mRNAs. ADAR1 expression and the pattern of the 5-HT(2C)R mRNA editing rapidly changed in response to IFN-alpha, leading to the dominant expression of the 5-HT(2C)R-VSI isoform predicted to have reduced G-protein coupling functions. Our results support the hypothesis that 5-HT(2C)R mRNA editing has causative relevance in the pathophysiology of depression associated with cytokine therapy.
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PMID:Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. 1509 87

The precise mechanisms governing the direct effect of IFN-beta, including apoptosis induction, are not yet fully understood. To gain a better insight into these mechanisms, we investigated the signaling pathways focusing particularly on interferon regulatory factor 1 (IRF-1) and IRF-2 in glioblastoma cell lines. Furthermore, we attempted to determine whether or not IRF-1 and IRF-2 act as additional prognostic indicators in diffusely infiltrating astrocytomas (DIA). We first assessed the cytotoxic effects of IFN-beta based on a cell growth study and modified MTT assay, and then quantified the apoptosis using a sandwich enzyme immunoassay following IFN-beta treatment in the cell lines, U-87MG, T98G, and A-172. Subsequently, we carried out an analysis of apoptosis-related molecules as evaluated by densitometric analysis of Western blots, focusing on IRF-1 and IRF-2, and two major initiator caspases, caspase-8 and caspase-9. Furthermore, we assessed the expression of type I IFN receptor, IRF-1, and IRF-2 using immunohistochemical techniques in 63 DIA (15 of WHO grade II, 18 of grade III, and 30 of grade IV), and analyzed their impact on prognosis. An increase in apoptosis was apparent after 48 h of IFN-beta treatment (1 x 10(4) IU/ml) in T98G but not in U-87MG or A-172. IFN-beta treatment for 6 h significantly enhanced the expression of IRF-1 in all three cell lines. However, an enhanced expression of IRF-2 was observed only in the not-most-sensitive, non-apoptosis-induced U-87MG and A-172. While minimal processing of caspase-8 was noted in the three cell lines throughout the experiment, caspase-9 activation was observed in the apoptosis-detected T98G after 48 h of treatment, as indicated by a 1.33-fold increase (P=0.037). On the other hand, the IRF-1 LI and IRF-1/IRF-2 LI ratio were greater in low-grade DAI, and were negatively correlated with the histopathological grade in DIA (P=0.017 and P=0.001, respectively). Furthermore, the IRF-1/IRF-2 LI ratio was negatively correlated with the MIB-1 LI in DIA (P=0.004), and represented an independent and most powerful determinant of overall survival compared to other conventional prognostic factors (P=0.018). However, the relation was not statistically significant when only patients with high-grade DIA were assessed. Our findings suggest that up-regulation of IRF-1 and IRF-2 might be an important determinant of susceptibility to IFN-beta mediated cytotoxicity including apoptosis. Furthermore, the IRF-1/IRF-2 LI ratio may reflect the proliferative state of DIA and constitute an important prognostic marker in DIA. Thus, IRF-1 and IRF-2 could represent one of the therapeutic target sites for the regulation of cell growth in DIA.
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PMID:Therapeutic implications of interferon regulatory factor (IRF)-1 and IRF-2 in diffusely infiltrating astrocytomas (DIA): response to interferon (IFN)-beta in glioblastoma cells and prognostic value for DIA. 1618 22

Glioblastomas are highly vascularized tumors and anti-angiogenic strategy is one of the most promising therapeutic approaches to treat brain tumors. Interferon alpha (IFN-alpha) as a single agent or combined with standard chemo-therapy has been shown to inhibit various tumors, but the effect of combination anti-angiogenic therapy on brain tumors has not been well studied. We determined the optimal dose and schedule of pegylated IFN-alpha (PEG-IFN-alpha) against U-87MG human glioblastoma cells growing orthotopically in nude mice, since several clinical trials reported that PEG-IFN-alpha administered at higher or lower doses was less effective. The group treated two times per week with injections of 10 KU of PEG-IFN-alpha for 4 weeks showed significant decreases in cell proliferation and angiogenesis. Moreover, the optimal dose and schedule of PEG-IFN-alpha determined in this study and combined with paclitaxel treatment potently inhibited tumor growth in vivo. The mechanisms of the significant therapeutic effects were most likely caused by directly inhibiting cell proliferation and angiogenesis, and rendering apoptosis increased. Specifically PEG-IFN-alpha/paclitaxel combination induced apoptosis of tumor-associated endothelial cells more than that of tumor cells. These results suggest that optimal biological dosage and scheduling of PEG-IFN-alpha and paclitaxel combination is a potent strategy for glioblastoma patients as a new synergistic anti-endothelial treatment.
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PMID:Synergistic effect and condition of pegylated interferon alpha with paclitaxel on glioblastoma. 1668 40

Induction of proinflammatory cytokines in response to malignant cells is an integral component of immune response to control tumor development. However, recent evidences have suggested that tumor cells may evade the immune system and exploit inflammatory responses to enhance its own growth. An exemplary example is the highly invasive and tumor necrosis factor (TNF)alpha-resistant glioblastoma, whose growth is associated with TNFalpha expression. We thus examined whether the tumor takes advantage of TNFalpha overexpression to enhance its invasiveness. To delineate the contribution of inflammation in tumor migration, we demonstrated that the role of proinflammatory cytokines on matrix metalloproteinases-3 (MMP-3) expression, and its consequent effects on the invasiveness of a human glioma cell-line, T98G. By using Matrigel Invasion Chamber, T98G cell migration was significantly enhanced in response to TNFalpha. In contrast, interferon-gamma (IFN gamma) reduced both basal and TNFalpha-enhanced cell invasion. To investigate the mechanisms involved, we demonstrated that TNFalpha upregulated mRNA and protein expression of MMP-3 in T98G cells, whereas IFN gamma downregulated the MMP-3 expression. The role of MMP-3 in glioma invasiveness was further confirmed by transfecting MMP-3 siRNA in T98G to abrogate the TNFalpha-enhanced cell invasion. To delineate the mechanisms further, we showed that IFN gamma exerts an inhibitory effect on the binding of TNFalpha-activated Ets-1 and NF kappa B to their respective enhancer elements found in MMP-3 promoter. In summary, our results indicated that TNFalpha enhances the invasiveness of T98G glioma cells through MMP-3 induction, and such enhancement of cell migration can be inhibited by IFN gamma.
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PMID:Interferon-gamma regulation of TNFalpha-induced matrix metalloproteinase 3 expression and migration of human glioma T98G cells. 1752 Jun 72

MicroRNA (miR)-221 and miR-222 are frequently upregulated in various types of human malignancy including glioblastoma. Previous studies have identified some targets of miR-221 and miR-222, such as p27 and p57. Inter-relationship between miR-221 and miR-222 expression and global mRNA expression remains elusive. Here we knocked down miR-221 and miR-222 expression and found 158 differentially expressed genes with 2-fold changes in U251 glioma cells by microarray analysis. Using the KEGG pathway databases and BioCarta, we found that the IFN-alpha signaling pathway was the most significant pathway modulated by differentially expressed genes. STAT1 and STAT2 are core proteins in the IFN-alpha signaling pathway. By Western blotting and immunofluorescence, we found that STAT1 and STAT2 expression and phosphorylation were upregulated in U251 cells with knocked-down miR-221/222. Furthermore, tyrosine phosphorylation of STAT1 and STAT2 was present in the nucleus after repression of miR-221/222 expression in U251 cells. These data indicate for the first time a mechanism involving STAT1/2 upregulation under the transcriptional control of INF-alpha signaling after knockdown of miR-221/222 cluster in U251 glioma cells.
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PMID:Global changes of mRNA expression reveals an increased activity of the interferon-induced signal transducer and activator of transcription (STAT) pathway by repression of miR-221/222 in glioblastoma U251 cells. 2042 75


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