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 apoptosis in tumor cells is an important determinant in the outcome of therapy. Molecular details of the apoptosis pathway, however, are still poorly defined. The recently discovered WAF1/CIP1 gene is a potent inhibitor of cyclin-dependent kinases and a mediator of tumor-suppressor p53-dependent apoptosis by DNA damage. In addition, WAF1/CIP1 expression is shown to be triggered through the p53-independent pathway. The relationship between WAF1/CIP1 and p53-independent apoptosis by DNA damage, however, remains unclear. In this study, we show that WAF1/CIP1 was induced in p53-dependent apoptosis of U87-MG glioma cells by cis-diamminedichloroplatinum (cisplatin), and overexpression of WAF1/CIP1 induced apoptosis in U87-MG cells without cisplatin treatment. In contrast, the p53-independent apoptosis of GB-1 glioma cells by cisplatin did not express WAF1/CIP1. Overexpression of WAF1/CIP1 inhibited DNA synthesis in GB-1 cells, but did not induce apoptosis. Interestingly, WAF1/CIP1 increased the susceptibility of GB-1 cells to cisplatin-induced apoptosis. These results suggest that overexpression of WAF1/CIP1 may have potential for the treatment of tumors with non-functional p53.
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PMID:WAF1/CIP1 increases the susceptibility of p53 non-functional malignant glioma cells to cisplatin-induced apoptosis. 880 2

Wild-type human p53 gene was transfected into the human glioma cell line T-98G. Transfectants were then isolated and characterized for growth potential and differentiation phenotype. Growth suppression, overexpression of GFAP, and accumulation in G1 phase were more commonly observed in transfectants than in T-98G cells. p21WAF1/CIP1 was overexpressed in transfectants, and the binding of PCNA and CDK 2 to p21WAF1/CIP1 were increased in transfectants. These results suggested the roles of p21WAF1/CIP1, PCNA, and CDK2 in regulation of differentiation in glioma cells and the gene transfer of wild-type p53 may be effective for the control of glial differentiation in glioma cells.
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PMID:Induction of differentiation by wild-type p53 gene in a human glioma cell line. 912 May 41

p21WAF1/CIP1 is a downstream mediator of p53 and mediates growth arrest by inhibiting the action of G1 cyclin-dependent kinases. Since cellular differentiation is frequently characterized by G1 arrest, we examined whether p21WAF1/CIP1 overexpression would induce growth suppression and differentiation in p53-defective human glioma cells. Overexpression of p21WAF1/CIP1 resulted in an accumulation of cells in G1, altered morphology, growth arrest and cell differentiation. The extent of cell differentiation correlated with the level of p21WAF1/CIP1 as well as of proliferating cell nuclear antigen, cyclin E, and cdk 2, which associates with p21WAF1/CIP1. Our data suggest that gene transfer of p21WAF1/CIP1 may arrest glioma cell growth in vivo by committing malignant glioma cells to a pathway of terminal differentiation.
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PMID:Overexpression of p21WAF1/CIP1 induces cell differentiation and growth inhibition in a human glioma cell line. 946 69

Dexamethasone (DEX)-mediated inhibition of drug-induced, but not CD95 ligand-induced, apoptosis in malignant glioma cells correlates with wild-type p53 status. Here, we examined mechanisms underlying DEX-mediated protection from apoptosis. DEX did not induce p53 expression in two p53 wild-type cell lines (U87MG, LN-229) and did not alter drug-induced p53 accumulation. Forced expression of temperature-sensitive p53val135 in mutant conformation failed to prevent accumulation of endogenous wild-type p53 but acted in a transdominant negative manner to inhibit p53-mediated, camptothecin-induced p21WAF1/CIP1 expression. p53val135-transfected cells retained responsiveness to DEX at restrictive temperature, suggesting that p53 activity is not required for cytoprotection. Forced expression of wild-type p53val135 abrogated the protective effect of DEX, suggesting redundant cytoprotective effects of DEX and p53. Indeed, DEX induced moderate accumulation of p21WAF1/CIP1 in U87MG, LN-229 and p53 mutant LN-18 cells, but not in p53 mutant LN-308 or T98G cells. LN-18 is also the p53 mutant cell line with the best cytoprotective response to DEX. p21WAF1/CIP1 accumulation occurred in the absence of changes in p21WAF1/CIP1 mRNA expression. Wild-type p53 was not required for this DEX effect since DEX induced p21WAF1/CIP1 accumulation in p53val135-transfected LN-229 cells, too. DEX failed to induce p21WAF1/CIP1 expression or cytoprotection in untransformed rat astrocytes. The same lack of modulation of p21WAF1/CIP1 expression and drug toxicity was observed in p21(+/+), p21(+/-) and p21(-/-) human colon carcinoma cells. Paradoxically, while only p21(+/+) and p21(+/-) mouse embryonic fibroblasts showed enhance p21WAF1/CIP1 levels after exposure to DEX, only p21(-/-) fibroblasts were protected from drug toxicity by DEX. The present study links DEX-mediated protection from cancer chemotherapy to a p53-independent pathway of regulating p21WAF1/CIP1 expression in glioma cells but this effect appears to cell type-specific.
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PMID:Dexamethasone-mediated protection from drug cytotoxicity: association with p21WAF1/CIP1 protein accumulation? 979 34

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
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PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66

The role of p21WAF1/CIP1 (p21) in DNA repair and apoptosis following gamma-irradiation remains controversial. In this study the influence of p21 on the radiosensitivity of human brain tumors was investigated. Resected tumors were stained immunohistochemically for p21. Expression of p21 in astrocytic tumors was high, but it was low in medulloblastomas, germinomas, and primary malignant lymphomas. Glioma and medulloblastoma cell lines were transfected with pcDNA/p21 to cause p21 overexpression, then tumor-cell colony formation and apoptosis were assessed following gamma-irradiation of the transfected and nontransfected cells. Overexpression of p21 enhanced clonogenic survival and suppressed apoptosis after gamma-irradiation in human brain tumor cell lines with or without p53 protein deficiency. Radioresistance was acquired when p21 was overproduced in the glioma cell lines irrespective of p53 status.
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PMID:Relationship between expression of p21WAF1/CIP1 and radioresistance in human gliomas. 1042 56

Alterations of the p53 gene have been attributed a major role in the development and resistance to therapy of several human cancers. Accumulation of p53 in tumor cells may result from mutations associated with prolonged half-life or from stabilization of wild-type p53 by different mechanisms. To address the role of p53 accumulation in the response of malignant glioma cells to radiochemotherapy, we expressed the p53 mutant p53(V143A) in five human malignant glioma cell lines with different genetic and functional p53 status. Accumulation of p53(V143A) modulated proliferation in three and clonogenicity in four of five cell lines without a clear pattern with regard to their endogenous p53 status. p53(V143A) inhibited the camptothecin-induced accumulation of p21(WAF1/CIP1) in cell lines with p53 functional wild-type activity, but not in cell lines lacking p53 activity, consistent with a transdominant-negative effect of p53(V143A). Irradiation induced a moderate G2/M arrest in all cell lines, irrespective of the p53 status, that was unaffected by p53(V143A). Radiosensitivity as well as sensitivity to BCNU, teniposide (VM26), topotecan, vincristine, Taxol, and cisplatin both in cytotoxic cell death and in clonogenic cell death was unchanged in p53(V143A)-transfected cells with few exceptions. These data do not support the hypothesis that accumulation of mutant p53 is a major determinant of the response to adjuvant radiochemotherapy in human malignant glioma cells.
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PMID:Accumulation of mutant p53(V143A) modulates the growth, clonogenicity, and radiochemosensitivity of malignant glioma cells independent of endogenous p53 status. 1058 66

Malignant gliomas of astrocytic origin have commonly expressed several features such as alterations in the tumor-suppressor gene p53 or p16 or the acquisition of telomerase activity, which are distinctive from astrocytes. Therefore, restoration of the tumor-suppressor gene or telomerase inhibition is expected to provide a cure for malignant gliomas. We have recently demonstrated that the treatment with a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-5A-anti-hTR) inhibited the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hTR combined with the restoration of p53 or p16 gene. In this study, we evaluated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21WAF1/CIP1, or p16CDKN2 gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase-dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against subcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressing the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treatment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic potential for malignant gliomas with mutant p53. For tumors exhibiting wild-type p53, it may be useful to treat with 2-5A-anti-hTR. Gene Therapy (2000) 7, 2071-2079.
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PMID:Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53. 1122 87

Transient expression of the tumor suppressor gene p53 via adenoviral-mediated gene transfer induces apoptosis in glioma cells expressing mutant p53, while causing cell cycle arrest in cells with wild-type p53. To determine whether a change in p53 status of a wild-type p53-expressing cell line such as U-87 MG would alter its apoptotic resistant phenotype in response to Ad-p53 infection, we generated cell lines U-87-175.4 and U-87-175.13 via retroviral-mediated gene transfer of the p53 (175H) mutant into the U-87 MG parental line. Control cell lines U-87-Lux.6 and U-87-Lux.8 were also generated and express the reporter gene luciferase. Both U-87-175.4 and U-87-175.13, but not control cell lines, exhibited morphology characteristic of apoptosis after Ad-p53 infection. Furthermore, expression of other p53 mutants (248W, 273H) in U-87 MG also sensitized cells to Ad-p53-induced apoptosis. Apoptosis was confirmed by TUNEL and cell cycle analysis. Several p53 response genes were examined in cells infected with Ad-p53, and among these, BCL2, p21WAF1/CIP1, CPP32/caspase 3, and PARP showed differences in expression between U87-175 and U87-Lux cell lines. Taken together, our data demonstrate that the introduction of p53 mutants in U-87 MG promotes an apoptotic response in association with adenoviral-mediated wild-type p53 gene transfer. These results underscore the importance of glioma p53 genotype for predicting tumor response to p53-based gene therapy.
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PMID:Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis. 1129 82

Malignant gliomas are highly resistant tumors against gamma-irradiation and contained overexpression of p21WAF1/CIP1 (p21). Overexpression of p21 enhanced clonogenic survival and suppressed apoptosis after gamma-irradiation in human brain tumor cell lines with or without p53 protein deficiency. The effect of antisense oligonucleotide to p21 against the gamma-irradiation-induced apoptosis and cytotoxicity in malignant glioma cell lines was examined. Antennapedia homeodomain internalization peptide was used as an insertion vector. The high transfection efficiency of Antennapedia homeodomain internalization peptide joined with antisense oligonucleotide was observed. The pretreatment with antisense oligonucleotide enhanced the gamma-irradiation-induced apoptosis and cytotoxicity in radioresistant glioma cells. p21 may represent an important new target for radiosensitization protocols, possibly involving antisense oligonucleotide directed against p21.
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PMID:Overcoming of radioresistance in human gliomas by p21WAF1/CIP1 antisense oligonucleotide. 1138 7


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