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)

Calphostin C acts at the regulatory domain as a highly selective inhibitor of protein kinase C (PKC), and staurosporine acts at the catalytic domain as a nonspecific PKC inhibitor. The authors investigated the capacity of calphostin C and staurosporine to promote apoptotic fragmentation of DNA in four human glioma cell lines. The exposure of glioma cell lines to 100 nM calphostin C for 2 to 8 hours induced a decrease in particulate PKC activities and exposure for 16 to 24 hours produced a concentration-dependent increase in internucleosomal DNA cleavage on agarose gel electrophoresis. In addition, the human glioma cells showed the classic morphological features of apoptosis: cell shrinkage, nuclear condensation, and the formation of apoptotic bodies. A 24-hour exposure to staurosporine failed to induce internucleosomal DNA fragmentation at concentrations generally used to achieve maximum inhibition of enzyme activity (50 nM) but promoted fragmentation at considerably higher concentration (more than 200 nM). Deoxyribonucleic acid fragments obtained from cells exposed to 100 nM calphostin C for 16 to 24 hours possessed predominantly 5'-phosphate termini, consistent with the action of a Ca++/Mg(++)-dependent endonuclease. Northern and Western blot analyses revealed that the exposure to 100 nM calphostin C for 4 hours failed to alter bcl-2 transcript and protein, but exposure for more than 8 hours decreased the amount of bcl-2 transcript and protein. Together, these observations suggest that calphostin C is capable of inducing apoptotic DNA fragmentation and cell death in a highly concentration dependent manner in human glioma cells and that the apoptosis is closely associated with the decrease in transcription and translation of bcl-2.
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PMID:Apoptosis of human glioma cells in response to calphostin C, a specific protein kinase C inhibitor. 749 Jun 14

The bcl-2 protooncogene encodes a 26-kD protein that extends cell survival by blocking apoptosis. This protein has been found to be overexpressed in neoplastic neural cell lines, although its expression in reactive and neoplastic astrocytes in vivo has not been well characterized. The authors hypothesized that bcl-2 oncoprotein expression in gliomas might be positively correlated with the tumor's degree of malignancy. Sixty-three gliomas of various subtypes and histological grades were immunostained by bcl-2 protein and the percentage of positive cells was quantitatively assessed. All tumors contained neoplastic cells that were immunoreactive for the bcl-2 protein (range of cell positivity 1%-53%). It was found that bcl-2 expression did not vary significantly as a function of tumor subtype or grade (p < 0.1, one-way analysis of variance (ANOVA) on ranks) as compared to the cell proliferation marker Ki-67 (MIB-1) in which a very significant correlation with tumor grade was noted (p < 0.0000001, one-way ANOVA on ranks). In fact, the highest percentage of bcl-2 immunoreactive cells was noted in low-grade gliomas, that is, in juvenile pilocytic astrocytomas and oligoastrocytomas. The specificity of bcl-2 overexpression was also assessed in 10 nonneoplastic lesions associated with prominent reactive astrocytosis. In nine of these cases (90%), bcl-2-positive reactive astrocytes were observed, often in large numbers, whereas relatively few Ki-67 immunoreactive cells were noted. The authors conclude that bcl-2 oncoprotein expression as assessed immunohistochemically does not correlate with glial tumor type or grade and its overexpression is not confined only to neoplastic conditions. Instead, the finding of robust bcl-2 expression in low-grade glial tumors and in reactive astrocytes warrants the inference that resistance to apoptosis is a nonspecific finding in astrocytes associated with both reactive and neoplastic conditions.
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PMID:Expression of bcl-2 in reactive and neoplastic astrocytes: lack of correlation with presence or degree of malignancy. 749 Jun 15

Fas/APO-1 is a transmembrane protein of the nerve growth factor/TNF alpha receptor family which signals apoptotic cell death in susceptible target cells. We have investigated the susceptibility of seven human malignant glioma cell lines to Fas/APO-1-dependent apoptosis. Sensitivity to Fas/APO-1 antibody-mediated cell killing correlated with cell surface expression of Fas/APO-1. Expression of Fas/APO-1 as well as Fas/APO-1-dependent cytotoxicity were augmented by preexposure of human malignant glioma cells to IFN gamma and TNF alpha. Further, pretreatment with TGF beta 2, IL1 and IL8 enhanced Fas/APO-1 antibody-induced glioma cell apoptosis whereas other cytokines including TNF beta, IL6, macrophage colony-stimulating factor, IL10 and IL13 had no such effect. None of the human malignant glioma cell lines was susceptible to TNF alpha-induced cytotoxicity. Fas/APO-1 antibody-sensitive glioma cell lines (n = 5), but not Fas/APO-1 antibody-resistant glioma cell lines (n = 2), became sensitive to TNF alpha when co-treated with inhibitors of RNA and protein synthesis. Resistance of human glioma cells to Fas/APO-1 antibody-mediated apoptosis was mainly related to low level expression of Fas/APO-1 and appeared not to be linked to overexpression of the anti-apoptotic protooncogene, bcl-2. Given the resistance of human malignant glioma to surgery, irradiation, chemotherapy and immunotherapy, we propose that Fas/APO-1 may be a promising target for a novel locoregionary approach to human malignant glioma. This strategy gains support from the demonstration of Fas/APO-1 expression in ex vivo human malignant glioma specimens and from the absence of Fas/APO-1 in normal human brain parenchyma.
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PMID:Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. 752 90

The majority of human malignant glioma cells express Fas/APO-1 and are susceptible to Fas/APO-1 antibody-mediated apoptosis in vitro. The sensitivity of Fas/APO-1-positive glioma cell lines to Fas/APO-1 antibody-mediated killing correlates inversely with the constitutive expression of the antiapoptotic protooncogene bcl-2. Here we report that BCL-2 protein expression of human glial tumors in vivo correlates with malignant transformation in that BCL-2 immunoreactive glioma cells were more abundant in WHO grade III/IV gliomas than in grade I/II gliomas. Fas/APO-1 antibody-sensitive human glioma cell lines stably transfected with a murine bcl-2 cDNA acquired resistance to Fas/APO-1 antibody-mediated apoptosis. Forced expression of bcl-2 also attenuated TNF alpha-mediated cytotoxicity of glioma cell lines in the presence of actinomycin D and cycloheximide and conferred partial protection from irradiation and the cancer chemotherapy drugs, cisplatin and BCNU. Preexposure of the glioma cell lines to the cytokines, IFN gamma and TNF alpha, which sensitize for Fas/APO-1-dependent killing, partially overcame bcl-2-mediated rescue from apoptosis, suggesting that multimodality immunotherapy involving cytokines and Fas/APO-1 targeting might eventually provide a promising approach to the treatment of human malignant gliomas.
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PMID:Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. 753 58

It has recently been shown that the bcl-2 gene is involved in the growth and development of certain tumors by suppressing apoptosis. To explore the possible involvement of the Bcl-2 protein in gliomas, three human glioma cell lines (T98G, A172, and U251) were examined for the presence of this protein. It could be documented by confocal laser microscopy that the Bcl-2 protein was localized mainly in mitochondria and nuclear membrane of T98G cells. Flow cytometric analysis revealed that 71-87% of the cultured glioma cells expressed the Bcl-2 protein. Treatment of U251 cells with ACNU for 24 h induced increased Bcl-2 protein expression; induction was dose dependent. Exposure of T98G and A172 cells to ACNU did not affect their Bcl-2 protein levels. Southern blot analysis revealed no chromosomal translocation in the cells studied. These findings suggest that Bcl-2 protein overexpression in glioma cells may partly contribute to tumor growth and tolerance to chemotherapeutic agents.
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PMID:Induced expression and subcellular localization of the Bcl-2 protein in cultured glioma cells. 789 19

Gene transfection experiments demonstrated that over-expression of the s-myc gene under the control of a human metallothionein promoter induced apoptosis in cells such as rat and human glioma cells. In contrast to c-Myc-mediated apoptosis requiring withdrawal of serum growth factors, s-myc expression induced apoptosis in glioma cells in the presence of 10% fetal calf serum. Whereas, s-Myc-mediated apoptosis was suppressed in proportion to the increase of bcl-2 expression as seen in c-Myc mediated apoptosis. The s-myc gene was expressed in rat embryo cells being committed to differentiate to hypertrophic chondrocytes which undergo programmed cell death. CAT assay demonstrated that in the NH2-terminal region, the s-Myc protein contains a domain structure required for expression of transactivation activity that is approximately six times higher than that of c-Myc. Therefore, these findings strongly suggest that s-Myc may play an important role in transcription regulation of a set of genes whose expression induces programmed cell death in vitro and in vivo.
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PMID:The s-Myc protein having the ability to induce apoptosis is selectively expressed in rat embryo chondrocytes. 803 17

Increasing the susceptibility of tumor cells to apoptotic cell death following chemotherapy is of importance to the outcome of cancer treatment. Although the tumor suppressor gene p53 is required for efficient induction of apoptosis by chemotherapeutic agents, it is not the only apoptosis mediator gene. The molecular mechanisms mediating apoptosis following chemotherapy via p53-dependent or p53-independent pathways remain unclear. We show here that cis-diamminedichloroplatinum (cisplatin) induces the expression of interleukin-1 beta-converting enzyme (ICE), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, in murine and human malignant glioma cells during apoptosis regardless of their p53 status. Furthermore, overexpression of the murine ICE gene induces apoptosis in these tumor cells. The apoptosis induced by cisplatin treatment or murine ICE overexpression can be suppressed by the tetrapeptide ICE inhibitor Ac-YVAD-CMK or the apoptosis inhibitors bcl-2 or bcl-2-related bcl-XL gene. These findings suggest that ICE may mediate apoptosis induced by chemotherapy, and its induction could represent a novel approach for the effective treatment of malignant glioma.
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PMID:Interleukin-1 beta-converting enzyme mediates cisplatin-induced apoptosis in malignant glioma cells. 852 9

The p53 tumor-suppressor gene is the most commonly mutated gene in cancer. However, p53 gene alterations are infrequent in renal-cell cancer (RCC). Bcl-2 has been shown to inhibit apoptosis triggered by wild-type p53 and an inverse correlation between Bcl-2 expression and p53 mutation has been observed in breast cancer and glioma. To characterize the expression of bcl-2 in RCC and its relationship to the p53 status, we analyzed 25 RCCs by immunohistochemistry for Bcl-2 and p53, Southern hybridization for bcl-2, and PCR-SSCP and sequencing for p53. Positive Bcl-2 staining was detected in 17 of 25 RCCs, whereas positive p53 staining was seen in only 1. Amplification of bcl-2 or p53 mutation was not detected in any of the tumors. Bcl-2 protein was expressed in all 7 RCC cell lines examined. Only one of the 7 lines had p53 mutation. These results suggest that overexpression of bcl-2, rather than p53 mutation, may prevent apoptosis during RCC development.
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PMID:Frequent expression of Bcl-2 in renal-cell carcinomas carrying wild-type p53. 862 Dec 51

The bax protein regulates apoptosis in a cellular pathway that involves both bcl-2 and p53, two molecules associated with human glioma tumorigenesis. We therefore evaluated the possibility that BAX functions as a glioma tumor suppressor gene. Somatic cell hybrid panels, fluorescence in situ hybridization and cosmid mapping localized the BAX gene to 19q13.3, approximately 300 kb centromeric to HRC. Thus BAX maps to the region of chromosome 19 most frequently deleted in gliomas. Routine and pulsed-field gel electrophoresis/Southern blotting studies, however, failed to reveal large-scale deletions or rearrangements of the BAX gene in gliomas. In addition, single strand conformation polymorphism analysis of all six BAX exons and flanking intronic sequences did not disclose mutations in 20 gliomas with allelic loss of the other copy of 19q. A C/T polymorphism was detected in intron 3 and was common in the general population. Therefore, although BAX maps to the glioma candidate region on the long arm of chromosome 19, BAX is probably not the 19q glioma tumor suppressor gene.
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PMID:The BAX gene maps to the glioma candidate region at 19q13.3, but is not altered in human gliomas. 864 Jul 22

Basic fibroblast growth factor (bFGF) is mitogenic to neuroectoderm- and mesoderm-derived cells and is a potent angiogenic factor. Abundant amounts of this factor and its receptor are detected in human glioma tissues and cells, and bFGF in glioma is thought to be involved in autonomous cell growth as an autocrine growth factor. A neutralizing mouse monoclonal antibody (MAb) against bFGF, 3H3 MAb, has been shown to inhibit both in vitro and in vivo growth of human glioma cell lines. This study shows that the human glioma cell lines U-87MG and U-251MG, which express high levels of bFGF and its receptor, can be induced to undergo apoptosis when cultured with 3H3 MAb. It is also demonstrated that 3H3 MAb can cause apoptosis in the same glioma cells that were transplanted into nude mice. Furthermore, enforced overexpression of bcl-2 protein by gene transfection prevented 3H3 MAb-induced apoptosis of glioma cells. It is concluded that induction of apoptosis by the neutralizing antibody is a promising therapeutic strategy for glioma.
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PMID:Apoptosis of human glioma cells in vitro and in vivo induced by a neutralizing antibody against human basic fibroblast growth factor. 892 97


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