Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of several benzodiazepines (diazepam, clonazepam, Ro 15-1788 and Ro 5-4864) on cell proliferation of 2 human gliomas were estimated in vitro by means of [3H]-thymidine uptake assay. It was found that all tested benzodiazepines suppressed [3H]-thymidine incorporation into the DNA of glioma cells, the effects being stronger in case of peripheral-type benzodiazepine receptor ligands. The results indicated that benzodiazepines might exert an antiproliferative action on glioma tumour cells growth.
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PMID:Inhibition of cell proliferation of human gliomas by benzodiazepines in vitro. 313 26

High affinity "peripheral-type" benzodiazepine binding sites were detected in an interleukin-1 (IL-1) responsive murine thymoma cell line EL4.NOB-1. Exposure of these cells to IL-1 over a period of at least 24 hr resulted in down-regulation of the binding sites. This effect was inhibited by the IL-1 receptor antagonist (IL-1RA) which in these cells inhibits IL-1 binding to the type I IL-1 receptor. Phorbol myristate acetate (PMA), another activator of EL4.NOB-1 cells, had an opposite effect to IL-1 in that it increased binding site expression dramatically suggesting different mechanisms of action for these two effectors. IL-1 produced a similar response in the rat glioma cell line C6 whereas PMA was ineffective. Such modulation of the peripheral-type benzodiazepine receptor may provide an insight into its physiological role and its possible participation in IL-1 actions in different cells.
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PMID:Interleukin-1 and phorbol myristate acetate modulate the peripheral-type benzodiazepine receptor in lymphocytes and glial cells. 839 35

The peripheral-type benzodiazepine receptor is found primarily on the outer mitochondrial membrane and consists of three subunits: the 18kDa isoquinoline binding protein, the 32kDa voltage-dependent anion channel, and the 30kDa adenine nucleotide transporter. The current study evaluates the potential importance of peripheral-type benzodiazepine receptor expression in glioma cell tumorigenicity. While previous studies have suggested that peripheral-type benzodiazepine receptor-binding may be relatively increased in tumor tissue and cells, so far, little is known about the relationships between peripheral-type benzodiazepine receptor density and factors underlying tumorigenicity. In the present study, we found in glioma cell lines (C6, U87MG, and T98G), that peripheral-type benzodiazepine receptor ligand-binding density is relatively high for C6 and low for T98G, while U87MG displays intermediate levels. Cell growth of these cell lines in soft agar indicated that high levels of peripheral-type benzodiazepine receptor-binding were associated with increased colony size, indicative of their ability to establish anchorage independent cell proliferation. Potential causes for differences in tumorigenicity between these cell lines were suggested by various cell death and proliferation assays. Cell death, including apoptosis, appeared to be low in C6, and high in T98G, while U87MG displayed intermediate levels in this respect. Cell proliferation appeared to be high in C6, low in T98G, and intermediate in U87MG. In conclusion, our study suggests that relatively high peripheral-type benzodiazepine receptor-binding density is associated with enhanced tumorigenicity and cell proliferation rate. In particular, apoptosis appears to be an important tumorigenic determinant in these glioma cell lines. Moreover, application of PBR-specific ligands indicated that PBR indeed are functionally involved in apoptosis in glioma cells.
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PMID:Peripheral-type benzodiazepine receptor density and in vitro tumorigenicity of glioma cell lines. 1527 76

The peripheral-type benzodiazepine receptor (PBR) is an 18-kDa high affinity drug- and cholesterol-binding protein that is involved in various cell functions, including cell proliferation and apoptosis. PBR was shown to be overexpressed in certain types of malignant human tumors and cancer cell lines, correlating with enhanced tumorigenicity and cell proliferation rates. The present study was conducted in order to further define the role of PBR in cancer and to extend our recent findings regarding the possible anticancer effects of the standardized Ginkgo biloba extract EGb 761. Treatment with EGb 761 decreased PBR mRNA levels and inhibited the proliferation of breast, glioma and hepatocarcinoma cell lines, further corroborating our previous contention that its mechanism of action is through the modification of PBR expression. In vivo treatment with Ginkgo biloba extract led to dose-dependent decreases in xenograft growth of both MDA-MB-231 breast cancer and U-87 glioma cell lines in nude mice, although the effects were not maintained after 50 days of treatment in the latter. The results obtained in MDA-MB-231 xenografts indicated pronounced inhibition of tumor growth, verified by MRI imaging. These results were obtained using a modified experimental protocol where the animals were treated with the extract before cell inoculation. Although an exact role for PBR in relation to the initiation and progression of various types of cancer remains to be defined, our results indicate that PBR overexpression in certain cancer cells is related to an aggressive phenotype. Since EGb 761 treatment opposes this aggressive phenotype by decreasing PBR overexpression, it could be useful in preventing or treating cancer invasiveness and metastasis.
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PMID:Cancer-related overexpression of the peripheral-type benzodiazepine receptor and cytostatic anticancer effects of Ginkgo biloba extract (EGb 761). 1647 73

Fluorescent ligands for the peripheral-type benzodiazepine receptor (PBR) featuring the 7-nitrobenz-2-oxa-1,3-diazol-4-yl moiety were synthesized, based on N,N-dialkyl-2-phenylindol-3-ylglyoxylamides, a potent, selective class of PBR ligands previously described by us. All the new ligands are moderately to highly potent at the PBR, with a complete selectivity over the central benzodiazepine receptor. Results from fluorescence microscopy showed that these probes specifically labeled the PBR at the mitochondrial level in C6 glioma cells.
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PMID:New fluorescent 2-phenylindolglyoxylamide derivatives as probes targeting the peripheral-type benzodiazepine receptor: design, synthesis, and biological evaluation. 1722 85

It has been shown that the atypical antipsychotic drug clozapine increases the levels of the neurosteroid allopregnanolone in the rat brain. The 18 kDa translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, has been demonstrated to be involved in the process of steroid biosynthesis, in peripheral steroidogenic tissues as well as in glia cells in the brain. In the current study, we investigated the influence of chronic treatment with clozapine and other antipsychotics (thioridazine,sulpiride and risperidone) on TSPO binding in cell cultures and rat tissues. Clozapine significantly increased TSPO binding density in C6 rat glioma cells and in MA-10 mouse Leydig tumor cells, while the antipsychotic sulpiride had no effect on TSPO binding density in both cell lines. In addition, clozapine, but not sulpiride, significantly increased progesterone synthesis by MA-10 Leydig tumor cells. In an animal experiment, male Sprague-Dawley rats were treated with clozapine (20 mg/kg), risperidone (0.5 mg/kg), thioridazine (20 mg/kg), or sulpiride (20 mg/kg) for 21 days, followed by 7 days of withdrawal. Clozapine induced significant increases in TSPO binding in brain and peripheral steroidogenic tissues, whereas the other antipsychotics did not show such pronounced effects on TSPO binding. Our results suggest that TSPO may be involved in the modulation of steroidogenesis by clozapine.
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PMID:The influence of clozapine treatment and other antipsychotics on the 18 kDa translocator protein, formerly named the peripheral-type benzodiazepine receptor, and steroid production. 1756 80

Gliomas are one of the most malignant cancers. The molecular bases regulating the onset of such tumors are still poorly understood. The translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is a mitochondrial permeability transition (MPT)-pore protein robustly expressed in gliomas and involved in the regulation of apoptosis and cell proliferation. TSPO expression levels have been correlated with tumor malignancy. Here we describe the production of C6 rat glioma cells engineered to over-express the TSPO protein with the aim of providing the first direct evidence of a correlation between TSPO expression level and glioma cell aggressiveness. We observed that TSPO potentiates proliferation, motility and transmigration capabilities as well as the ability to overcome contact-induced cell growth inhibition of glioma cells. On the whole, these data demonstrate that TSPO density influences metastatic potential of glioma cells. Since several data suggest that TSPO ligands may act as chemotherapeutic agents, in this paper we also demonstrate that TSPO ligand-induced cell death is dependent on TSPO density. These findings suggest that the use of TSPO ligands as chemotherapeutic agents could be effective on aggressive tumor cells with a high TSPO expression level.
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PMID:TSPO over-expression increases motility, transmigration and proliferation properties of C6 rat glioma cells. 1819 Jul 98

For some malignant cancers even combined surgical, radiotherapeutic and chemotherapeutic approaches are not curative, indeed, in certain tumour types even a modest survival benefit is difficult to achieve. There are various biological reasons which underlie this profound resistance but the propensity of cancer cells to repair breaks caused by DNA-damaging radiation and cytotoxic drugs is of major significance in this context. Such highly resistant tumours include the malignant gliomas which are intrinsic to and directly affect the brain and spinal cord. In evaluating approaches which do not elicit tumour cell death directly by DNA damage, it is intriguing to consider mitochondrially mediated apoptosis as a potentially effective alternative. Since the mitochondrial membrane potentials in cancer cells are frequently reduced in comparison with those of non-neoplastic cells this allows a window of opportunity for small molecule agents to enter the tumour cell mitochondria and reduce oxygen consumption with subsequent release of cytochrome c and activation of a caspase pathway to apoptosis which is cancer cell specific. In the quest for agents which can selectively destroy neoplastic cells in this manner, whilst leaving normal adjacent cells intact, various tricyclic drugs have come under scrutiny. In a range of laboratory assays we, and others, have established that certain cancers and, in particular, malignant glioma, are intrinsically sensitive to this approach. We have also established the cellular, molecular and biochemical mechanisms underlying this process. While such archival tricyclics as the antidepressants, clomipramine and amitriptyline, have been used in these experiments their commercial development in cancer therapy has not been forthcoming and their clinical use in glioma has been confined to anecdotal cases. In addition, the dose-dependant role of agents such as anticonvulsants and steroids commonly used in glioma patients in modulating efficacy of the tricyclics is a matter for continued investigation. Other ways of targeting the mitochondrion for cancer therapy include exploitation of the 18kDa translocator protein (peripheral-type benzodiazepine receptor) within the mitochondrial permeability transition pore and enzymatic or molecular modification of a species of ganglioside (GD3/GD3(A)) expressed on the surface of neoplastic cells which are determinants of mitochondrially mediated apoptosis. It is hoped that such approaches may lead to clinical programmes which will improve the prognosis for patients suffering from highly resistant neoplasms.
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PMID:Approaches to mitochondrially mediated cancer therapy. 1820 19