Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma cells exhibit several forms of sensitivity to extracellular calcium (Ca(o)) that might be conferred by the Ca(o)-sensing receptor (CaR) that is intimately involved in the maintenance of Ca(o) homeostasis by various cell types. This receptor is expressed in human glioblastoma cell line, U87, and here we show that CaR activators stimulate a Ca(2+)-activated potassium (K(+)) channel (CAKC) with a conductance of 140 pS. The responses to CaR activators, however, were blunted in U87 cells transfected with a CaR bearing an inactivating mutation (R185Q) that has previously been shown to exert a dominant negative (DN) action on the wild type receptor. Raising Ca(o) from 0.75 to 2.0 mM or addition of a polycationic CaR agonist, each activated CAKC in nontransfected wild type and empty vector-transfected U87 cells, while they had little or no effect on channel activity in cells expressing the DN CaR (DN-CaR cells). In nontransfected wild type and empty vector-transfected cells, the specific 'calcimimetic' CaR activator, NPS R-467, stimulated the channel, while its less active stereoisomer, NPS S-467, did not. In DN-CaR cells, in contrast, NPS R-467, had no effect on channel activity, suggesting defective coupling of the CaR to this ion channel. CaR-mediated stimulation of these K(+) channels could lead to membrane repolarization and related changes in cellular function under normal conditions. Since the R185Q mutation in the CaR produces a more severe phenotype in humans than most inactivating mutations of this receptor, some of its clinical consequences could potentially result from abnormal CaR-dependent channel functioning.
Brain Res Mol Brain Res 2000 Sep 15
PMID:Defective extracellular calcium (Ca(o))-sensing receptor (CaR)-mediated stimulation of a Ca(2+)-activated potassium channel in glioblastoma cells transfected with a dominant negative CaR. 1103 50

Glioblastoma (GB), the relatively frequent and most malignant form of primary brain tumor, is fatal within 1 to 2 years of onset of symptoms, despite conventional therapy. Molecular therapy promises to be an effective and possibly curative treatment. Several molecular strategies have been tested, either in animal models or clinical trials. These include: prodrug activating systems, introduction of tumor suppressor or cell-cycle-related genes, inhibition of growth factors and/or their receptors, inhibition of neovascularization, immunomodulatory maneuvers, oncolytic viruses and inhibition of matrix metalloproteinases. Of special interest for the development of optimal molecular therapy of GB, is the choice of the most efficient and least toxic gene vectors (adenovirus, retrovirus, herpes simplex virus), the route of administration of the therapeutic agent (intratumoral with or without debulking and intracarotid), avoidance of collateral damage to the perineoplastic neuropil and adequate preclinical studies. The ultimate molecular therapy will probably involve the application of multiple simultaneous (combinatorial) therapeutic modalities. The safety and efficiency of these in humans can only be judged by properly controlled therapeutic trials.
Curr Opin Mol Ther 1999 Oct
PMID:Molecular therapy for glioblastoma. 1124 60

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

Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
Mol Cancer Ther 2004 Feb
PMID:Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. 1498 53

Glioblastoma is one of the most radioresistant tumors. Exposure of cells to ionizing radiation leads to formation of reactive oxygen species (ROS) that are associated with radiation-induced cytotoxicity. ROS scavengers, therefore, are one of the important factors in protecting cells against ROS injury during ionizing radiation exposure. In the present study, we isolated and established a radioresistant variant clone (RRC) from U251 human glioblastoma cell line and investigated the potential role of antioxidant enzymes in radioresistance of the glioblastoma cell line. RRC showed a higher radioresistance than the parent cell line as measured by clonogenic survival assay and showed delayed G2/M arrest. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), glutathione reductase (GR), were activated up to 5-fold in RRC compared to the parent cells after radiation. In addition, RRC also had cross-resistance to the antitumor agent cisplatin. Therefore, radioresistance and cross-resistance to chemotherapeutic agent in RRC might be due to the highly coordinated activation of antioxidant enzymes rather than a single enzyme alone.
Int J Mol Med 2004 Jun
PMID:Increased expression of antioxidant enzymes in radioresistant variant from U251 human glioblastoma cell line. 1513 30

Glioblastoma is an aggressive brain tumor with a dismal prognosis. Gene therapy may offer a new option for the treatment of these patients. Several gene therapy approaches have shown anti-tumor efficiency in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. HSV-tk gene therapy has been the pioneering and most commonly used approach, but oncolytic conditionally replicating adenoviruses and herpes simplex virus mutant vectors, p53, interleukins, interferons, and antisense oligonucleotides have also been used. During the past few years, adenoviruses have become the most popular gene transfer vectors, and some recent randomized, controlled trials have shown significant anti-tumor efficacy in clinical use. However, efficient gene delivery into the brain still presents a major problem, and there is a lack of definitive phase III trials, which would avoid potential problems associated with a small number of patients, inadvertent patient selection, and overinterpretation of results based on a few long-time survivors. For clinical efficacy, median survival is one of the most rigorous endpoints. It is used here to evaluate the usefulness of various treatment approaches and current clinical status of gene therapy for malignant glioma.
Mol Ther 2005 Oct
PMID:Gene therapy for malignant glioma: current clinical status. 1609 72

Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.
Mol Ther 2005 Nov
PMID:Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma. 1615 Jun 49

The present study uses cell-based screening assays to assess the anticancer effects of targeting phosphatidylinositol 3-kinase-regulated integrin-linked kinase (ILK) in combination with small-molecule inhibitors of Raf-1 or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK). The objective was to determine if synergistic interactions are achievable through the use of agents targeting two key cell signaling pathways involved in regulating glioblastoma cancer. The phosphatidylinositol 3-kinase/protein kinase B (PKB)/Akt and the Ras/MAPK pathway were targeted for their involvement in cell survival and cell proliferation, respectively. The glioblastoma cell lines U87MG, SF-188, and U251MG were transiently transfected with an antisense oligonucleotide targeting ILK (ILKAS) alone or in combination with the Raf-1 inhibitor GW5074 or with the MEK inhibitor U0126. Dose and combination effects were analyzed by the Chou and Talalay median-effect method and indicated that combinations targeting ILK with either Raf-1 or MEK resulted in a synergistic interaction. Glioblastoma cells transfected with ILKAS exhibited reduced levels of ILK and phosphorylated PKB/Akt on Ser473 but not PKB/Akt on Thr308 as shown by immunoblot analysis. These results were confirmed using glioblastoma cells transfected with ILK small interfering RNA, which also suggested enhanced gene silencing when used in combination with U0126. U87MG glioblastoma cells showed a 90% (P < 0.05) reduction in colony formation in soft agar with exposure to ILKAS in combination with GW5074 compared with control colonies. A substantial increase in Annexin V-positive cells as determined by using fluorescence-activated cell sorting methods were seen in combinations that included ILKAS. Combinations targeting ILK and components of the Ras/MAPK pathway result in synergy and could potentially be more effective against glioblastoma cancer than monotherapy.
Mol Cancer Ther 2006 Mar
PMID:Combined inhibition of the phosphatidylinositol 3-kinase/Akt and Ras/mitogen-activated protein kinase pathways results in synergistic effects in glioblastoma cells. 1654 79

In an article presented in this issue of Molecular Pharmacology, Yacoub et al. (p. 589) examine the actions of 2-amino-N{4-5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-acetamide (OSU-03012) on both primary and glioblastoma cell lines. The authors found that OSU-03012 could induce tumor cell death by itself but also acted as a strong sensitizing agent to radiotherapy-induced cell death. Glioblastoma cells were also more sensitive to this compound than nontransformed astrocytes. Radiation-induced cell death was refractory to small interfering RNA-directed inhibition of PDK1 but not OSU-03012. These results indicate that OSU-03012, which has been thought to primarily mediate antitumor effects via the inhibition of PDK1, has actions independent of PDK1. Furthermore, the authors demonstrated that the effects of OSU-03012 were independent of ERB-B1-vIII and PTEN expression. These are important findings because they start to identify a new mechanism to sensitize glioblastoma cells and also suggest that OSU-03012 could be combined with existing inhibitors to further sensitize tumor cells. In glioblastoma cells, OSU-03012 seemed to induce apoptosis via endoplasmic reticulum stress-induced PERK-dependent signaling. OSU-03012-induced death of the glioblastoma was only weakly suppressed by the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp, suggesting that OSU-03012-induced cell death was largely caspase-independent. Overall, these are exciting results and suggest that new more effective treatment options may be obtainable for people suffering from these deadly tumors.
Mol Pharmacol 2006 Aug
PMID:OSU-03012 in the treatment of glioblastoma. 1667 57

Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and characterization of brain tumor-initiating cells supports the concept that transformed neural stem cells may seed glioblastoma. We previously identified a wide array of mesenchymal tissue transcripts overexpressed in a broad set of primary glioblastoma (de novo) tumors but not in secondary glioblastoma (derived from lower-grade) tumors, low-grade astrocytomas, or normal brain tissues. Here, we extend this observation and show that a subset of primary glioblastoma tumors and their derived tumor lines express cellular and molecular markers that are associated with mesenchymal stem cells (MSC) and that glioblastoma cell cultures can be induced to differentiate into multiple mesenchymal lineage-like cell types. These findings suggest either that a subset of primary glioblastomas derive from transformed stem cells containing MSC-like properties and retain partial phenotypic aspects of a MSC nature in tumors or that glioblastomas activate a series of genes that result in mesenchymal properties of the cancer cells to effect sustained tumor growth and malignant progression.
Mol Cancer Res 2006 Sep
PMID:Primary glioblastomas express mesenchymal stem-like properties. 1696 31


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