Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We have reported that valproic acid upregulates melatonin MT1 receptor expression in rat C6 glioma cells. In addition to its anticonvulsant and mood stabilizing properties, valproic acid can also inhibit the growth of cancer cells. Since the melatonin MT1 receptor has been implicated in the oncostatic action of melatonin on human MCF-7 breast cancer cells, the effect of valproic acid on its expression was examined in this cell line. Treatment of MCF-7 cells with valproic acid (0.5 or 1 mM) for 24 or 72 h caused a significant increase in melatonin MT1 receptor mRNA or protein expression, as shown by reverse transcription-polymerase chain reaction (RT-PCR) analysis and western blotting, respectively. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays revealed a concentration-dependent inhibition of MCF-7 cell proliferation by valproic acid (0.5, 1.0 or 5 mM), but melatonin (1 or 10 nM) was ineffective alone or in combination with valproic acid, in the first (MCF-7A) subline examined. However, in subsequent experiments using a different (MCF-7B) subline, which expressed higher levels of MT1 receptor mRNA and showed modest sensitivity to melatonin, a combination of this hormone with valproic acid produced a significant synergistic inhibition of cell proliferation. These findings indicate that clinically relevant concentrations of valproic acid upregulate melatonin MT1 receptor expression in human breast cancer cells. Moreover, the enhanced antiproliferative effect observed with a combination of valproic acid and melatonin suggests that a similar therapeutic approach may be beneficial in breast cancer.
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PMID:Human melatonin MT1 receptor induction by valproic acid and its effects in combination with melatonin on MCF-7 breast cancer cell proliferation. 1730 9

In 1999, Maniotis reported that blood vessels of highly aggressive uveal melanomas are formed by tumor cells instead of endothelial cells. He termed this novel concept in tumor vascularization vasculogenic mimicry (VM). Since then, VM has been seen in several malignant tumor types such as breast cancer, liver cancer, glioma, ovarian cancer, melanoma, prostate cancer, and bidirectional differentiated malignant tumors. Laser scanning confocal angiography, electron microscopy, and three-dimensional cell culture have confirmed the existence of VM. The molecular mechanisms that underlie VM are not fully clear, but metalloproteinases via their cleavage of laminin, VE-cadherin by promoting adherence of the VM channel wall to tumor cells, tumor cell dedifferentiation, and tumor microenvironment have been shown to play a role in VM. Zhang and co-workers have proposed a three-stage phenomenon among VM channels, mosaic blood vessels, and endothelium-dependent blood vessels, wherein all three patterns participate in tumor blood supply. Therapeutic strategies that target endothelial cells have no effect on tumor cells that engage in VM. VM-targeting strategies include suppressing tyrosine kinase activity and using a knockout EphA2 gene, downregulating VE-cadherin, using antibodies against human MMPs and the laminin 5gamma2 chain, and using anti-PI3K therapy. We review here the current status of research on VM; discuss molecular mechanisms of VM, factors affecting VM formation, and its clinical significance; and explore the development of novel tumor-targeted treatments that are based on the biochemical and molecular events that regulate VM.
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PMID:Vasculogenic mimicry: current status and future prospects. 1730 54

A new prototype of polymer-derived drug delivery system, the nanoconjugate Polycefin, was tested for its ability to accumulate in tumors based on enhanced permeability and retention (EPR) effect and receptor mediated endocytosis. Polycefin was synthesized for targeted delivery of Morpholino antisense oligonucleotides into certain tumors. It consists of units that are covalently conjugated with poly(beta-l-malic acid) (M(w) 50,000, M(w)/M(n) 1.3) highly purified from cultures of myxomycete Physarum polycephalum. The units are active in endosomal uptake, disruption of endosomal membranes, oligonucleotide release in the cytoplasm, and protection against enzymatic degradation in the vascular system. The polymer is biodegradable, non-immunogenic and non-toxic. Polycefin was also coupled with AlexaFluor 680 C2-maleimide dye for in vivo detection. Nude mice received subcutaneous injections of MDA-MB 468 human breast cancer cells into the left posterior mid-dorsum or intracranial injections of human glioma cell line U87MG. Polycefin at concentration of 2.5mg/kg was injected via the tail vein. In vivo fluorescence tumor imaging was performed at different time points, 0-180 min up to 24h after the drug injection. The custom-made macro-illumination imaging MISTI system was used to examine the in vivo drug accumulation in animals bearing human breast and brain tumors. In breast tumors the fluorescence signal in large blood vessels and in the tumor increased rapidly until 60 min and remained in the tumor at a level 6 times higher than in non-tumor tissue (180 min) (p<0.003). In brain tumors drug accumulated selectively in 24h without any detectable signal in non-tumor areas. The results of live imaging were corroborated histologically by fluorescence microscopic examination of various organs. In addition to tumors, only kidney and liver showed some fluorescent signal.
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PMID:Nanoconjugate based on polymalic acid for tumor targeting. 1737 17

Tumor progression and metastasis are complex processes involving intricate interplay among multiple gene products. Astrocyte elevated gene (AEG)-1 was cloned as an human immunodeficiency virus (HIV)-1-inducible and tumor necrosis factor-alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes (PHFA) by a rapid subtraction hybridization approach. AEG-1 down-regulates the expression of the glutamate transporter EAAT2; thus, it is implicated in glutamate-induced excitotoxic damage to neurons as evident in HIV-associated neurodegeneration. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells, and AEG-1 cooperates with Ha-ras to augment the transformed phenotype of normal immortal cells. Moreover, AEG-1 is overexpressed in >95% of human malignant glioma samples when compared with normal human brain. Overexpression of AEG-1 increases and siRNA inhibition of AEG-1 decreases migration and invasion of human glioma cells, respectively. AEG-1 contains a lung-homing domain facilitating breast tumor metastasis to lungs. These findings indicate that AEG-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers. Our recent observations indicate that AEG-1 exerts its effects by activating the nuclear factor kappa B (NF-kappaB) pathway and AEG-1 is a downstream target of Ha-ras and plays an important role in Ha-ras-mediated tumorigenesis. These provocative findings are intensifying interest in AEG-1 as a crucial regulator of tumor progression and metastasis and as a potential mediator of neurodegeneration. In this review, we discuss the cloning, structure and function(s) of AEG-1 and provide recent insights into the diverse actions and intriguing properties of this molecule.
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PMID:Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. 1739 30

Human NDRG2 (N-Myc downstream regulated gene 2) was identified as a candidate tumor suppressor gene due to its low expression in human glioma and other cancer tissues. However, the mechanisms that lead to inactivation of the NDRG2 gene remain unknown. In the present study, semi-quantitative RT-PCR and Western blot analysis were used to confirm that NDRG2 mRNA and protein levels are decreased in several cancer cell lines. We found heterozygous deletion of NDRG2 in MCF-7 cells, and showed that mutation (at -13bp (C>T)) and methylation of the NDRG2 promoter occurred in several cancer cell lines. Furthermore, mutation (-13bp (C>T)) of the NDRG2 core promoter significantly reduced NDRG2 activity. Finally, we showed that NDRG2 expression was decreased in several breast cancer tissues. Unexpectedly, changes in the NDRG2 gene were not observed. Here, we describe for the first time, the mechanisms involved in NDRG2 gene down-regulation.
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PMID:Promoter methylation, mutation, and genomic deletion are involved in the decreased NDRG2 expression levels in several cancer cell lines. 1747 Mar 64

The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
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PMID:Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. 1749 66

Chalcones are considered the precursors of flavonoids and have been identified as interesting compounds with antitumor properties. Boronic-chalcone derivatives are more toxic to breast cancer cells compared to normal breast cells. Here, we studied the antitumor activities of trans-4-lodo,4'-boranyl-chalcone (TLBC), which is a boronic-chalcone derivative, in several glioma cell lines. TLBC showed a dose-dependent inhibition with inhibitory concentration 50% value in the muM range (5.5-25.5 microM) in various glioma cell lines. Flow cytometric and western blot assay demonstrated that TLBC induced apoptosis independent of changes to the tumor suppressor p53. This cytotoxic effect was the caspase-dependent manner. Also, TLBC lowered levels of anti-apoptotic Bcl-2 and/or Bcl-X(L) protein in several of the cell lines. To examine the antitumor effect of TLBC in vivo, we used a malignant glioma xenograft model. This result showed that in the mice treated with TLBC at 20 mg/kg, mean tumor volume was reduced by 43.9% (P < 0.01) in comparison with the control group. Immunohistochemical and western blot analysis showed that Bcl-2 protein levels were decreased and Bax protein levels were slightly increased in the tumors injected with 20 mg/kg TLBC compared with the control tumors. Therefore, we conclude that TLBC may be a potential chemotherapeutic agent for human glioma.
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PMID:Trans-4-lodo,4'-boranyl-chalcone induces antitumor activity against malignant glioma cell lines in vitro and in vivo. 1753 Jan 76

A conjugable analogue of the benzodiazepine 4' '-chlorodiazepam (Ro5-4864), C6Ro5-4864 was synthesized to probe the binding sites of translocator protein (18 kDa; TSPO), previously known as the peripheral benzodiazepine receptor for molecular imaging. The amino group in this analogue allows universal conjugation to signaling molecules. Lissamine-C6Ro5-4864, synthesized from C6Ro5-4864 and a lissamine fluorescence dye, was investigated in this study. This imaging agent exhibited micromolar binding affinity (Ki = 2.6 microM) to TSPO and was successfully imaged in TSPO rich glioma and breast cancer cell lines. These findings suggest that C6Ro5-4864 may provide opportunities in imaging disease states where TSPO levels are affected, such as cancer and neurologic diseases.
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PMID:A novel conjugable translocator protein ligand labeled with a fluorescence dye for in vitro imaging. 1755 92

We previously reported phenotypic changes in human breast cancer cells following low-level magnetic field (MF) exposure. Here proteomic methods were used to investigate the biochemical effect of MF exposure in SF767 human glioma cells. Protein alterations were studied after exposure to 1.2 microTesla (microT) MF [12 milliGauss (mG), 60 Hertz (Hz)] +/- epidermal growth factor (EGF). SF767 cells were exposed for 3 h to sham conditions (<0.2 microT ambient field strength) or 1.2 microT MF (+/-EGF; 10 ng/ml). Solubilized protein fractions (sham; 1.2 microT; sham + EGF; 1.2 microT + EGF) were loaded for electrophoresis by 2D-PAGE and stained using a colloidal Coomassie blue technique to resolve and characterize the proteins. Protein patterns were compared across groups via Student's t-test using PDQUEST software. Cell profiles revealed significant alterations in the spot density of a subset of treated cells. Automated spot excision and processing was performed prior to peptide mass fingerprinting proteins of interest. Fifty-seven proteins from the detectable pool were identified and/or found to differ significantly across treatment groups. The mean abundance of 10 identified proteins was altered following 1.2 microT exposure. In the presence of EGF six proteins were altered after low magnetic field treatment by increasing (4) or decreasing (2) in abundance. The results suggest that the analysis of differentially expressed proteins in SF767 cells may be useful as biomarkers for biological changes caused by exposure to magnetic fields.
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PMID:Investigation of protein expression in magnetic field-treated human glioma cells. 1757 May 5

The heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a large family of proteins that play important roles in telomere biogenesis, DNA repair, cellular signaling, and the regulation of expression at both the transcriptional and translational levels. One of the most extensively studied hnRNP family members, hnRNP K, has been implicated in a variety of processes, including chromatin remodeling, transcription, splicing, and translation events. In this study, we analyzed processed HNRPK pseudogenes (HNRPK psi1-psi4) and coding sequences. HNRPK pseudogenes are apparently nonfunctional, and psi1 might correspond to transcripts from an ancestral gene. Phylogenetic and sequence analyses suggest that HNRP genes arose by duplication, and that new structural and sequence features expanded the functions of hnRNPs. The expression analysis of hnRNP K isoforms showed that isoform a is expressed in normal testis and in non-small cell lung cancer (NCI-H1155 NSCLC cell line), although the shorter isoform (isoform b) is expressed in different tumor cell lines (IM9 B-lymphoblastoid, Hs578T human breast cancer epithelial, T98G human glioma cell lines). Using molecular modeling, we obtained KH1 and KH3 models, which pointed to important residues for DNA-protein binding and no structural differences between isoforms a and b. To our knowledge, this is the first phylogenetic study including vertebrate HNRP genes and HNRPK pseudogenes, and the first report comparing the KH1 and KH3 domains of isoforms a and b of the hnRNP K protein. New investigations in tumor samples must be done to validate the differential expression observed here. The results shown are important because the hnRNP K protein might represent a new target for pharmacologic intervention in virus replication and cancer.
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PMID:Sequence and transcriptional study of HNRPK pseudogenes, and expression and molecular modeling analysis of hnRNP K isoforms. 1761 14


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