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)

Cyclin-dependent kinase inhibitors (CDKIs) are considered as novel anticancer agents because of their ability to induce growth arrest or apoptosis in tumour cells. It has not yet been fully determined, however, which CDKI is the best candidate for the treatment of malignant gliomas and whether normal brain tissues are affected by CDKI expression. Using recombinant adenoviral vectors that express CDKIs (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)), we compared the antitumour effect of CDKIs on malignant glioma cell lines (A172, GB-1, T98G, U87-MG, U251-MG and U373-MG). p27(KIP1) showed higher ability to suppress the growth of all tumour cells tested than other CDKIs. Interestingly, overexpression of p27(KIP1) induced autophagic cell death, but not apoptosis in tumour cells. On the other hand, p27(KIP1) overexpression did not inhibit the viability of cultured astrocytes (RNB) nor induced autophagy. Overall, our findings suggest that gene transfer of p27(KIP1) may be a promising approach for the therapy of malignant gliomas.
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PMID:Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells. 1269 96

Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to: 1. inhibit cell growth; 2. inhibit cell migration; 3. decrease expression of cyclin D1, CDK4 and p21; 4. induce apoptosis in cells with high levels of p27 expression; and 5. decrease the expression of the anti-apoptotic protein Bcl-2. The mechanism by which flavopiridol induces apoptosis is mitochondrial-mediated. We demonstrate by electron microscopy and immunohistochemistry that drug treatment induces mitochondrial damage that was accompanied by the release of cytochrome c into the cytosol together with the translocation of apoptosis inducing factor (AIF) into the nucleus. This finding in murine glioma cells differs from the mechanism of flavopiridolinduced cell death reported by us for human glioma cells (Alonso et al., Mol Cancer Ther 2003; 2:139) where drug treatment induced a caspase- and cytochrome c-independent pathway in the absence of detectable damage to mitochondria. In apoptotic human glioma cells only translocation of AIF into the nucleus occurred. Thus, the same drug kills different types of glioma cells by different mitochondrial-dependent pathways.
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PMID:Flavopiridol induces mitochondrial-mediated apoptosis in murine glioma GL261 cells via release of cytochrome c and apoptosis inducing factor. 1273 34

Gliomas are the most common tumors of the central nervous system and have a grave prognosis. Deletion of chromosome 10p15 is one of the most common chromosomal alterations in gliomas. Recently, a candidate tumor suppressor gene, KLF6, which is mapped to chromosome 10p, was found to be frequently mutated in prostate cancer. KLF6 is a zinc finger transcription factor and transactivates p21/WAF1/CIP expression. To elucidate the role of genetic alterations of KLF6 in gliomas, we analyzed the 4 exons of the gene by direct DNA sequencing in 155 gliomas. Of these, mutations of KLF6 were found in 9 of 76 (11.8%) glioblastomas multiforme, 2 of 28 (7.1%) anaplastic astrocytomas, 2 of 36 (5.5%) low-grade diffuse astrocytomas and in none of the 15 oligodendrogliomas. All 13 mutations were located in the transactivation domain and most of them affected either serine residues or codons next to serine residues. Of the 13 cases with KLF6 mutation, loss of heterozygosity (LOH) at the KLF6 locus was inferred from the LOH displayed by the flanking microsatellite markers in 11 cases. We conclude that mutations of the KLF6 gene play a role in the pathogenesis of astrocytic gliomas.
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PMID:KLF6, a putative tumor suppressor gene, is mutated in astrocytic gliomas. 1523 47

Gliomas are characterized by a deregulation of growth factor production and growth factor receptors expression, e.g. overproduction of the cytokine transforming growth factor-beta (TGF-beta) and overexpression/constitutive activation of receptors for the epidermal growth factor (EGF). Potential interactions of such growth factors and their signaling cascades could enhance the malignancy of these tumors. Therefore, we investigated the effects of TGF-beta and EGF alone and in combination on the proliferation of glioma cells cultivated from eight solid human WHO grade IV gliomas and one glioma cell line, analyzed the expression and intactness of the TGF-beta-signaling molecules Samd-4 and -2, and the phosphorylation of the EGF-signaling kinases ERK 1/2. The effects were divergent and complex: Whereas EGF mostly stimulated glioma cell proliferation, TGF-beta either enhanced, inhibited or had no significant effect on proliferation. In combination, co-stimulation and inhibition of the EGF-induced mitogenic activity could be observed. Smad-4/-2 were expressed in all glioma cells, one point mutation at base 1595 in Smad-4 did not affect its protein sequence. In part of the glioma cells, reduced phosphorylation of ERK 1/2 and expression of cyclin-dependent kinase inhibitor 1 or p21 was observed in co-stimulation experiments. These experiments show that TGF-beta can inhibit EGF-mediated effects only in some gliomas, whereas it enhances it in others. The interaction of both factors is very complex and varies between different gliomas.
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PMID:Interaction of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) in human glioma cells. 1282 16

Previous work from our laboratory demonstrated that PTEN regulates tumor-induced angiogenesis and thrombospondin 1 expression in malignant glioma. Herein, we demonstrated the first evidence that the systemic administration of a phosphatidylinositol 3'-kinase (PI3K) inhibitor (LY294002) has antitumor and antiangiogenic activity in vivo. We show that PTEN reconstitution diminished phosphorylation of AKT, induced the transactivation of p53 (7.5-fold induction) and increased the expression of p53 target genes, p21(waf-1) and insulin-like growth factor binding protein 3 in glioma cells. PTEN and LY294002 induced p53 activity in human brain endothelial cells, suggesting that PTEN and PI3K pathways can suppress the progression of cancer through direct actions on tumor and endothelial cells. The capacity of PTEN and LY294002 to inhibit U87MG or U373MG glioma growth was tested in an ectopic skin and orthotopic brain tumor model. LY294002 inhibited glioma tumor growth in vivo, induced tumor regression, decreased the incidence of brain tumors, and blocked the tumor-induced angiogenic response of U87MG cells in vivo. These data provide evidence that both PTEN and PI3K inhibitors regulate p53 function and display in vivo antiangiogenic and antitumor activity. These results provide evidence that the two tumor suppressor genes, PTEN and p53, act together to block tumor progression in vivo. Our data provide the first preclinical evidence for the in vivo efficacy for LY294002 in the treatment of malignant gliomas.
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PMID:PTEN and phosphatidylinositol 3'-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. 1283 45

Death receptor-mediated apoptosis of human malignant glioma cells triggered by CD95 ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) share several features, including processing of multiple caspases and mitochondrial cytochrome c release. We here report that CD95L-induced cell death is inhibited by sulfasalazine (SS) in all of four human glioma cell lines, both in the absence and presence of cycloheximide (CHX). Coexposure to CD95L and SS prevents the CD95L-evoked processing of caspases 2, 3, 8 and 9, the release of cytochrome c from mitochondria, and the loss of BCL-x(L) protein. This places the protective effect of SS proximal to most known events triggered by the CD95-dependent signaling pathway in glioma cells. CD95L promotes the accumulation of nuclear factor kappa B (NF-kappaB) in the nucleus and induces the DNA-binding activity of NF-kappaB assessed by electrophoretic mobility shift assay. The total levels of p50, p65 and IkappaBalpha remain unchanged, but the levels of phosphorylated IkappaBalpha and of nuclear p65 increase, in response to CD95L. IkappaBalpha phosphorylation as well as nuclear NF-kappaB translocation and DNA binding are blocked by SS. However, unlike SS, dominant-negative IkappaBalpha (IkappaBdn) does not block apoptosis, suggesting that SS inhibits CD95L-mediated apoptosis in an NF-kappaB-independent manner. In contrast to CD95L, the cytotoxic effects of Apo2L/TRAIL are enhanced by SS, and SS facilitates Apo2L/TRAIL-evoked caspase processing, cytochrome c release, and nuclear translocation of p65. These effects of SS are nullified in the presence of CHX, suggesting that the effects of SS and CHX are redundant or that enhanced apoptosis mediated by SS requires protein synthesis. IkappaBdn fails to modulate Apo2L/TRAIL-induced apoptosis. Similar effects of SS on CD95L- and Apo2L/TRAIL-induced apoptosis are observed in MCF-7 breast and HCT116 colon carcinoma cells. Interestingly, HCT cells lacking p21 (80S14(p21-/-)) are only slightly protected by SS from CD95L-induced apoptosis, but sensitized to Apo2L/TRAIL-induced apoptosis, indicating a link between the actions of SS and p21. Thus, SS modulates the death cascades triggered by CD95L and Apo2L/TRAIL in opposite directions in an NF-kappaB-independent manner, and SS may be a promising agent for the augmentation of Apo2L/TRAIL-based cancer therapies.
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PMID:NF-kappaB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/TRAIL-dependent death signaling pathways in human malignant glioma cells. 1293 82

CP-31398 is a prototype small molecule that stabilizes the active conformation of p53 and promotes p53 activity in cancer cell lines with mutant or wild-type p53. Here, we report that CP-31398 induces p53 reporter gene activity and p21 expression in all of 11 glioma cell lines harboring wild-type or mutant p53, but not in p53-null LN-308 cells. Upon prolonged exposure to CP-31398, all glioma cell lines undergo caspase-independent and bcl-x(L)-insensitive cell death with EC(50) concentrations of 10-36 microM. By comparing p53 wild-type U87MG and p53-null LN-308 cells expressing the temperature-sensitive p53(V135A) mutant, we delineate two pathways of CP-31398-induced cell death: an early, p53-dependent pathway that requires (new p53) protein synthesis and a late, p53-independent pathway characterized by aurintricarboxylic acid -sensitive calcium release and epiphenomenal free radical formation. Post-transcriptional repression of p53 synthesis by an intracellularly transcribed short interfering RNA confirmed the presence of these two pathways of cell death. These observations point out some of the liabilities of CP-31398 as a prototype p53-based therapeutic and define a rationale for further refinement of small molecules that specifically target the p53 pathway, but lack the p53-independent effects.
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PMID:CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. 1461 47

Malignant gliomas are the most common primary brain tumors in adults, and the most malignant form, glioblastoma multiforme (GBM), is usually rapidly fatal. Most GBMs do not have p53 mutations, although the p53 tumor suppressor pathway appears to be inactivated. GBMs grow in a hypoxic and inflammatory microenvironment, and increased levels of the free radicals nitric oxide (NO) and superoxide () occur in these malignancies in vivo. Peroxynitrite (ONOO(-)) is a highly reactive molecule produced by excess NO and that can posttranslationally modify and inactivate proteins, especially zinc finger transcription factors such as p53. We demonstrated previously that GBMs have evidence of tyrosine nitration, the "footprint" of peroxynitrite-mediated protein modification in vivo, and that peroxynitrite could inhibit the specific DNA binding ability of wild-type p53 protein in glioma cells in vitro. Here we show that both authentic peroxynitrite and SIN-1 (3-morpholinosydnonimine hydrochloride), a molecule that decomposes into NO and to form peroxynitrite, can inhibit wild-type p53 function in malignant glioma cells. Concentrations of peroxynitrite associated with a tumor inflammatory environment caused dysregulation of wild-type p53 transcriptional activity and downstream p21(WAF1) expression.
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PMID:Inactivation of wild-type p53 protein function by reactive oxygen and nitrogen species in malignant glioma cells. 1469 79

Antineoplastons work as molecular switches, which regulate expression of genes p53 and p21 through demethylation of promoter sequences and acetylation of histones. They also inhibit the uptake of growth-critical amino acids, such as 1-glutamine and 1-leucine in neoplastic cells. Phase II trials indicate efficacy of antineoplastons in low-grade glioma, brain stem glioma, high-grade glioma, adenocarcinoma of the colon, and hepatocellular carcinoma. The best results were observed in children with low-grade glioma, where 74% of patients obtained objective response, and in patients with adenocarcinoma of the colon with liver metastases whose survival rate of more than 5 years is 91% versus 39% in controls on chemotherapy. Gene array studies will explain antineoplaston-induced changes in gene expression.
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PMID:The present state of antineoplaston research (1). 1531 59

The regulator of fibroblast growth factor 2 (FGF-2) transcription (RFT) has been reported to be a transcriptional repressor of FGF-2 and induce glioma cell death by its overexpression. Here we report that RFT regulates cell cycle as well as apoptosis by a novel mechanism. RFT expressed in some glioma cell lines, U138MG and T98G, but neither in U87MG nor U251MG. Overexpressed RFT-induced apoptosis in U87MG and U138MG with functioning-type p53 but neither in U251MG nor T98G with non-functioning-type p53. Administration of FGF-2 failed to prevent RFT-induced apoptosis. Overexpression of RFT caused G1-S arrest and upregulated both the phosphorylation of p53 at Ser-15 and the expression level of p21(Waf1). Furthermore, RNAi knockdown of p53 abolished RFT-induced apoptosis in U87MG. Taken together, our results support that RFT regulates G1-S transition and apoptosis via p53/p21(Waf1) pathway.
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PMID:Overexpression of RFT induces G1-S arrest and apoptosis via p53/p21(Waf1) pathway in glioma cell. 1508 25


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