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)

Induction of differentiation is an attractive approach to the management of infiltrative tumors such as malignant glioma. Here, we report that lovastatin and phenylacetate induce apoptosis, but fail to induce differentiation, in malignant glioma cell lines and untransformed rat astrocytes. Lovastatin and phenylacetate promote p21 accumulation but fail to induce cell cycle arrest. BCL-2 gene transfer inhibits apoptosis induced by lovastatin but not apoptosis induced by phenylacetate. Wild-type p53 gene transfer promotes lovastatin-induced apoptosis in p53 wild-type LN-229 cells but not in p53 mutant T98G cells. Phenylacetate-induced apoptosis is attenuated by wild-type p53 gene transfer in both cell lines. Neither lovastatin nor phenylacetate modulate glioma cell sensitivity to CD95 ligand-induced apoptosis or cancer chemotherapy. Thus, this study provides no rationale for clinical trials of lovastatin or phenylacetate in the differentiation therapy of malignant glioma. We conclude that neoplastic glioma cells as well as untransformed rat astrocytes are refractory to the induction of differentiation by lovastatin and phenylacetate.
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PMID:Lovastatin and phenylacetate induce apoptosis, but not differentiation, in human malignant glioma cells. 1130 20

Aquaporin-4 (AQP4), a mercury-insensitive water channel protein, is abundant in the central nervous system and is localized in astrocytes and ependymal cells. AQP4 is speculated to maintain the homeostasis of intracellular and extracellular water in the brain, but little is known about the mechanism of induction of its expression. To investigate the expressional regulation of AQP4, we analyzed changes in its expression during chemically induced differentiation of embryonal carcinoma cells (P19) to neuronal and astrocytic cells, and during the cell cycle of glioma cells. After exposure to retinoic acid for 4 days AQP4 mRNA expression started at the initiation of astrocytic differentiation of P19 cells at 6 days, and increased markedly by 21 days. AQP4 expression was parallel to that of GFAP, a marker intermediate filament of astrocytes. In glioma cell lines, AQP4 mRNA was not detected in the growing phase, but was induced when the cell cycle was arrested at G0/G1 by transient expression of p21. Although quiescent astrocytes in the G0/G1-phase cultured under the serum-free condition exhibited a high expression of AQP4, serum supplement moved them to the S-phase and markedly decreased the AQP expression. These results suggest that AQP4 expression may be induced not only at the initiation of astrocytic differentiation of neural stem cells, but also at the G0/G1-phase during the cell cycle of astrocytes.
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PMID:Regulation of aquaporin-4 expression in astrocytes. 1131 79

We examined the effect of p53 inactivation on the response of U87MG glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These studies were motivated by three observations: (a) some human astrocytomas are sensitive to BCNU and some are resistant; (b) chemosensitive astrocytomas are more likely to be found in young adults whose tumors are more likely to harbor a p53 mutation; and (c) mouse astrocytes lacking the p53 gene are more sensitive to BCNU than wild-type cells. Here, we observed that p53 inactivation by transfection with pCMV-E6 sensitized U87MG cells to BCNU. Compared with control U87MG-neo cells with intact p53 function, the clonogenic survival of U87MG-E6 cells exposed to BCNU was reduced significantly. In U87MG-E6 cells, sensitization to BCNU was associated with failure of p21(WAF1) induction, transient cell cycle arrest in S phase, accumulation of polyploid cells, and significant cell death. In contrast, resistance to BCNU in U87MG-neo cells was associated with up-regulation of p53, prolonged induction of p21(WAF1), sustained cell cycle arrest in S phase, and enhancement of DNA repair. U87MG cells with disrupted p53 function were less able to repair BCNU-induced DNA damage and survive this chemotherapeutic insult. The question arises of whether p53 dysfunction might be a chemosensitizing genetic alteration in human astrocytic gliomas.
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PMID:Inactivation of p53 sensitizes U87MG glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea. 1135 39

Extensive infiltration of normal brain tissue and suppression of anti-tumor immune surveillance mediated by molecules such as transforming growth factor-beta (TGF-beta) are key biological features that contribute to the malignant phenotype of human gliomas. Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) is an anti-allergic compound used clinically to control atopic and fibrotic disorders. These effects are attributed to the suppression of TGF-beta1 synthesis and interference with growth factor-mediated proliferation and migration of fibroblasts and vascular smooth muscle cells. Here, we show that tranilast inhibits DNA synthesis and proliferation of human malignant glioma cells and promotes p21 accumulation in the absence of cytotoxicity. Further, tranilast reduces the release of TGF-beta1 and TGF-beta2 by glioma cells and inhibits migration, chemotactic responses and invasiveness. These effects are not associated with a reduction of alpha(v)beta(3) integrin expression at the cell surface but appear to involve inhibition of matrix metalloproteinase-2 expression and activity. Neither the tranilast-mediated inhibition of proliferation nor the inhibition of migration was counteracted by supplementation with exogenous TGF-beta. Finally, tranilast administered orally inhibited the growth of experimental 9L rat gliomas and reduced expression of TGF-beta2 in vivo. We conclude that tranilast might be a useful therapeutic agent for the treatment of human malignant glioma because of a TGF-beta-independent abrogation of the malignant phenotype of proliferation, migration and invasiveness and because of the antagonism of TGF-beta-associated immunosuppression.
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PMID:N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor-beta relesase and reduces migration and invasiveness of human malignant glioma cells. 1139 21

The therapeutic efficacy of standard cancer treatments such as chemotherapy may be improved if they are combined with gene-therapy. Less than 30% of patients with glioblastoma multiforme respond to adjuvant chemotherapy. Actively dividing cells are generally more sensitive to chemotherapy than are non-dividing cells. To determine whether forced cell-cycle progression selectively sensitizes tumor cells to alkylating agents, we examined the effects of overexpressing the E2F-1 protein (a positive regulator of cell-cycle progression) on the sensitivity of two malignant human glioma cell lines, U-251 MG and D-54 MG, to BCNU and temozolomide. Treating these cells with 20-35 microM BCNU or 20-30 microM temozolomide resulted in 50% growth inhibition (IC50) within 4 or 6 days, respectively. By contrast, cells that were first induced to overexpress E2F-1 protein by infection with an adenoviral vector had IC50s that were 37-50% lower. Conversely, transferring the cyclin-dependent kinase inhibitors p16 and p21 to the cells, also by adenoviral infection, produced 3 to 4-fold increases in chemoresistance. Cell-cycle analyses showed that the combination of E2F-1 overexpression and treatment with BCNU or temozolomide increased the proportion of cells in S phase, but the combination of p16 or p21 overexpression and drug treatment reduced the proportion of cells in S phase. These observations suggest that overexpression of genes that positively control cell-cycle progression may be useful for increasing the sensitivity of glioma cells to alkylating agents.
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PMID:Adenovirally-mediated transfer of E2F-1 potentiates chemosensitivity of human glioma cells to temozolomide and BCNU. 1144 52

Adenoviral chimeric tumor suppressor 1 (CTS1) gene transfer was evaluated as a novel approach of somatic gene therapy for malignant glioma. CTS1 is an artificial p53-based gene designed to resist various pathways of p53 inactivation. Here, we report that an adenovirus encoding CTS1 (Ad-CTS1) induces growth arrest and loss of viability in all glioma cell lines examined, in the absence of specific cell cycle changes. In contrast, an adenovirus encoding wild-type p53 (Ad-p53) does not consistently induce apoptosis in the same cell lines. Electron microscopic analysis of Ad-CTS1-infected glioma cells reveals complex cytoplasmic pathology and delayed apoptotic changes. Ad-CTS1 induces prominent activation of various p53 target genes, including p21 and MDM-2, but has no relevant effects on BCL-2 family protein expression. Although Ad-CTS1 strongly enhances CD95 expression at the cell surface, endogenous CD95/CD95 ligand interactions do not mediate CTS1-induced cell death. This is because Ad-CTS1 promotes neither caspase activation nor mitochondrial cytochrome c release and because the caspase inhibitors, z-val-Ala-DL-Asp-fluoromethylketone (zVAD)-fmk or z-Ile-Glu-Thr-Asp- fluoromethylketone (z-IETD)-fmk, do not block CTS1-induced cell death. Ad-CTS1 synergizes with radiotherapy and CD95 ligand in killing glioma cells. In summary, Ad-CTS1 induces an unusual type of cell death that appears to be independent of BCL-2 family proteins, cytochrome c release, and caspases. CTS1 gene transfer is a promising strategy of somatic gene therapy for malignant glioma.
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PMID:Chimeric tumor suppressor 1, a p53-derived chimeric tumor suppressor gene, kills p53 mutant and p53 wild-type glioma cells in synergy with irradiation and CD95 ligand. 1147 23

Temozolomide (TMZ) produces O(6)-methylguanine in DNA, which in turn mispairs with thymine, triggering futile DNA mismatch repair (MMR) and ultimately cell death. We found previously that in p53-proficient human glioma cells, TMZ-induced futile DNA MMR resulted not in apoptosis but rather in prolonged, p53- and p21-associated G(2)-M arrest and senescence. Additionally, p53-deficient cells were relatively more TMZ resistant than p53-deficient glioma cells, which underwent only transient G(2)-M arrest before death by mitotic catastrophe. These results suggested that prolonged G(2)-M arrest might protect cells from TMZ-induced cytotoxicity. In the present study, we therefore focused on the mechanism by which TMZ induces G(2)-M arrest and on whether inhibition of such G(2)-M arrest might sensitize glioma cells to TMZ-induced toxicity. U87MG glioma cells treated with TMZ underwent G(2)-M arrest associated with Chk1 activation and phosphorylation of both cdc25C and cdc2. These TMZ-induced effects were inhibited by the Chk1 kinase inhibitor UCN-01. Although not in itself toxic, UCN-01 increased the cytotoxicity of TMZ 5-fold, primarily by inhibiting cellular senescence and increasing the percentage of cells bypassing G(2)-M arrest and undergoing mitotic catastrophe. In addition to enhancing TMZ-induced cytotoxicity in p53-proficient cells, UCN-01 also blocked TMZ-induced Chk1 activation and transient G(2)-M arrest in p53-deficient U87MG-E6 cells and similarly enhanced TMZ-induced mitotic catastrophe and cell death. Taken together, these results indicate that Chk1 links TMZ-induced MMR to G(2)-M arrest. Furthermore, inhibition of the cytoprotective G(2) arrest pathway sensitizes cells to TMZ-induced cytotoxicity and may represent a novel, mechanism-based means of increasing TMZ efficacy in both p53 wild-type and p53 mutant glioma cells.
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PMID:Abrogation of the Chk1-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. 1147 24

A noninvasive method for molecular imaging of the activity of different signal transduction pathways and the expression of different genes in vivo would be of considerable value. It would aid in understanding the role specific genes and signal transduction pathways have in various diseases, and could elucidate temporal dynamics and regulation at different stages of disease and during various therapeutic interventions. We developed and assessed a method for monitoring the transcriptional activation of endogenous genes by positron-emission tomography (PET) imaging. The HSV1-tk/GFP (TKGFP) dual reporter gene was used to monitor transcriptional activation of p53-dependent genes. A retrovirus bearing the Cis-p53/TKGFP reporter system was constructed in which the TKGFP reporter gene was placed under control of an artificial cis-acting p53-specific enhancer. U87 glioma and SaOS-2 osteosarcoma cells were transduced with this retrovirus and used to establish xenografts in rats. We demonstrated that DNA damage-induced up-regulation of p53 transcriptional activity correlated with the expression of p53-dependent downstream genes, such as p21, in U87 (wild-type p53), but not in SaOS-2 osteosarcoma (p53 -/-) cells. We showed that PET, with [(124)I]FIAU (2'-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-[(124)I]iodouracil) and the Cis-p53TKGFP reporter system, is sufficiently sensitive to image the transcriptional regulation of genes in the p53 signal transduction pathway. These imaging results were confirmed by independent measurements of p53 activity and the expression levels of downstream genes (e.g., p21) by using conventional molecular-biological assays. PET imaging of p53 transcriptional activity in tumor xenografts by using the Cis-p53TKGFP reporter system may be useful in assessing novel therapeutic approaches.
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PMID:Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo. 1148 88

The mutation and/or deletion of tumor suppressor genes have been postulated to play a major role in the genesis and the progression of gliomas. In this study, the functional expression and efficacy in tumor suppression of 3 tumor suppressor genes (p53, p21, and p16) were tested and compared in a rat GBM cell line (RT-2) after retrovirus mediated gene delivery in vitro and in vivo. Significant reductions in tumor cell growth rate were found in p16 and p21 infected cells (60 +/- 12% vs 66 +/- 15%) compared to p53 (35 +/- 9%). In vitro colony formation assay also showed significant reductions after p16 and p21 gene delivery (98 +/- 5% vs 91 +/- 10%) compared to p53 (50 +/- 18%). In addition, the tumor suppression efficacy were investigated and compared in vivo. Retroviral mediated p16 and p21 gene deliveries in glioblastomas resulted in more than 90% reductions in tumor growth (92 +/- 26% vs 90 +/- 22%) compared to p53 (62 +/- 18%). Tumor suppressor gene insertions in situ further prolonged animal survival. Overall p16 and p21 genes showed more powerful tumor suppressor effects than p53. The results were not surprising, as p16 and p21 are more downstream in the cell cycle regulatory pathway compared to p53. Moreover, the mechanism involved in each of their suppressor effects is different. This study demonstrates the feasibility of using tumor suppressor genes in regulating the growth of glioma in vitro and in situ.
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PMID:Comparisons of tumor suppressor p53, p21, and p16 gene therapy effects on glioblastoma tumorigenicity in situ. 1154 71

It was investigated whether there was a relationship between p53 p21 and p27 induction pathways in the cellular response of glioma cells to hyperthermia. Two glioma cell lines were employed. A-172 cells had the wild-type of p53, and U251 cells had the mutant-type of p53. An adenovirus harbouring wild-type p53 was also used for the overexpression. The protein induction by hyperthermia was monitored by Western blot analysis. In U251 cells, the expression of wild-type p53 and hyperthermia had an additional cytotoxic effect, but did not affect A-172 cells. Significant p21 accumulation by hyperthermia was recognized in A-172 cells, and was also recognized in p53-transduced U251 cells. On the other hand, the accumulation of p27 by hyperthermia was not seen in A-172 or U251 cells, and the exogenous expression of p53 did not affect the accumulation of p27 by hyperthermia in U251 cells. These findings suggest that the p53-p21 pathway is involved in the signal transduction after hyperthermia, rather than the p27 pathway.
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PMID:Accumulation of cell cycle regulatory proteins, p21 and p27, induced after hyperthermia in human glioma cells. 1171 66


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