UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chlorpromazine and other phenothiazine derivatives are neuroleptic drugs of widespread use for clinical situations beyond the realm of psychiatry, such as to control nausea, vomiting and intractable hiccups. The present study investigated in vitro different cytotoxic effects of chlorpromazine in cultures of mouse neuroblastoma cell line Neuro-2a exposed to different concentrations of this compound. Indicators assessed were cell proliferation by quantification of total protein content of the cell culture, lysosomal function evaluated by the relative uptake of neutral red cytosolic phosphofructokinase (PFK) and enolase (ENL) activities in glycolysis, mitochondrial succinate dehydrogenase (SDH) activity in the citric acid cycle, lysosomal beta-galactosidase (GAL) activity, and neuronal acetylcholinesterase activity. Marked inhibitory effects were found for cell proliferation and relative neutral red uptake; PFK, ENL and GAL activities had no significant differences from control. Stimulation was specifically detected on SDH and the Krebs cycle at concentrations up to 30 microM. Chlorpromazine did not have high toxicity for cytotoxic effects on lysosomes.
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PMID:Biochemical effects of chlorpromazine on mouse neuroblastoma cells. 1050 25

Although viral gene expression occurs in the peripheral nervous system during acute infection, bovine herpesvirus 1 (BHV-1) gene expression is extinguished, many neurons survive, and latency ensues. The only abundant viral transcript expressed during latency is the latency-related (LR) RNA, which is alternatively spliced in trigeminal ganglia during acute infection (L. Devireddy and C. Jones, J. Virol. 72:7294-7301, 1998). A subset of neurons express a protein encoded by the LR gene and the LR protein (LRP) is associated with cyclin-dependent kinase 2 (Cdk2)/cyclin complexes during productive infection (Y. Jiang, A. Hossain, M. T. Winkler, T. Holt, A. Doster, and C. Jones, J. Virol. 72:8133-8142, 1998). LR gene products inhibit cell cycle progression, perhaps as a result of LRP interacting with Cdk2/cyclin complexes. During acute infection, expression of cyclin A occurs in trigeminal ganglionic neurons (L. M. Schang, A. Hossain, and C. Jones, J. Virol. 70:3807-3814, 1996). Inappropriate expression of G(1)- and S-phase cyclins can initiate programmed cell death (PCD), apoptosis, in neurons, suggesting that LR gene products inhibit PCD. To test this hypothesis, we modified an assay to measure PCD frequency in transiently transfected cells. C(6)-ceramide, fumonisin B(1) (FB(1)), or etoposide was used to initiate PCD following transfection of cells with plasmids expressing LR gene products and the beta-galactosidase gene. Transfected cells that survived were quantified by counting beta-galactosidase-positive cells. Plasmids that expressed LR gene products promoted survival of monkey kidney (CV-1), human lung (IMR-90), or mouse neuroblastoma (neuro-2A) cells after induction of PCD. Plasmids with termination codons at the beginning of LR open reading frames or deletion of sequences that mediate splicing of LR RNA did not promote cell survival following PCD induction. We hypothesize that LR gene products play a role in promoting survival of postmitotic neurons during acute infection or reactivation.
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PMID:The latency-related gene of bovine herpesvirus 1 inhibits programmed cell death. 1055 83

The response of wild-type and genetically engineered neuroectodermal tumor (NET) cells to exogenous and endogenously synthesized nerve growth factor (NGF) was investigated. Differences in cell proliferation rate, neurite formation, and expression of NGF binding sites were quantitatively determined. Ecotropic retroviral vectors were used to transfer the genes for beta-galactosidase (beta-GAL) and NGF into wild-type C-1300 and Neuro-2A murine neuroblastoma (MNB) and rat pheochromocytoma (PC-12) cells. Conditioned media obtained from NET cells infected with the NGF gene contained biologically active NGF, whereas media from beta-GAL infected cells did not. Infection with the NGF vector induced a short-term decrease in cell proliferation rate and increased neurite formation in wild-type, substrate-adherent PC-12 and Neuro-2A MNB cells (P > 0.05). Incubation of wild-type C-1300, Neuro-2A MNB, and PC-12 cells with NGF (0-200 ng/ml) for 5 days significantly reduced proliferation rates in a concentration-dependent manner and increased neurite extrusion. All NGF-NET cells had a significantly diminished response to the antiproliferative action of exogenous NGF. Ligand binding assays with 125I-NGF demonstrated a marked reduction in the number of NGF binding sites on NGF-NET cells compared to wild type. The attenuated response of NGF-NET cells to exogenous NGF correlated positively with the down-regulation of NGF binding sites. In conclusion, beta-NGF gene transfer into wild-type NET cells induces the synthesis and secretion of NGF, temporarily decreases cell proliferation rate, increases neurite extrusion, down-regulates NGF binding sites, and reduces NET cell responsiveness to NGF. A putative role for NGF may be the modulation of NET cell proliferation and differentiation.
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PMID:Retroviral transfer of the beta-nerve growth factor gene into murine neuroectodermal tumor cells modulates cell proliferation rate, neurite formation, and NGF binding site expression. 1065 Aug 85

alpha-Synuclein is a key component of Lewy bodies found in the brains of patients with Parkinson's disease and two point mutations in this protein, Ala53Thr and Ala30Pro, are associated with rare familial forms of the disease. Several lines of evidence suggest the involvement of oxidative stress in the pathogenesis of nigral neuronal death in Parkinson's disease. In the present work we studied the effects of changes in the alpha-synuclein sequence on the susceptibility of cells to reactive oxygen species. Human dopaminergic neuroblastoma SH-SY5Y cells were stably transduced with various isoforms of alpha-synuclein and their survival following exposure to hydrogen peroxide or to the dopaminergic neurotoxin MPP(+) was assessed. Cells expressing the two point mutant isoforms of alpha-synuclein were significantly more vulnerable to oxidative stress, with the Ala53Thr engineered cells faring the worst. In addition, cells expressing C-terminally truncated alpha-synuclein, particularly the 1-120 residue protein, were more susceptible than control beta-galactosidase engineered cells. The present experiments indicate that point mutations and C-terminal truncation of alpha-synuclein exaggerate the susceptibility of dopaminergic cells to oxidative damage. Thus, these observations provide a pathogenetic link between alpha-synuclein aberrations and a putative cell death mechanism in Parkinson's disease.
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PMID:Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. 1079 59

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that has several functions, including the regulation of water and electrolyte secretion, hormone and cytokine release, bronchodilitation, and neurogenesis. VIP effects are mediated by specific G-protein coupled receptors. Three distinct receptor subtypes, with differing affinity for VIP, have been cloned and characterized as receptors 1 and 2 (VPAC1 and VPAC2) and pituitary adenylate cyclase activating polypeptide receptor (PAC1). Our laboratory has demonstrated that upregulation of VPAC1 in SK-N-SH neuroblastoma cells results in marked shift in cell type to the glial lineage with a corresponding loss of neuronal lineage and suppression of xenograft tumor growth. To understand the molecular mechanisms responsible for regulation of the VPAC1 gene in neuronal lineage, we have cloned and sequenced 2.6-kb of the 5'-flanking sequences of the human VPAC1 gene. Sequence analysis demonstrated that the human VPAC1 promoter sequence contains putative binding sites for several known transcription factors, including Sp1, NFkB, and cETS-1. To study the temporal and spatial expression pattern of human VPAC1 promoter sequences, we have generated transgenic mice expressing the bacterial beta-galactosidase gene under the control of the 2.6-kb 5'-flanking and promoter sequence of the human VPAC1 gene. Transgene expression was detected in brain, spinal cord, and lung in 14-day-old animals. Taken together, these results demonstrate that VPAC1 may play an important role in the nervous system, and suggest a role for VIP in neuronal differentiation.
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PMID:Regulation of vasoactive intestinal peptide receptor expression in developing nervous systems. 1119 20

Apoptosis Signal-regulating Kinase 1 (ASK1) is known to either induce apoptosis or differentiation in various cell lines of neuronal origin. We analyzed the effect of the constitutively active mutant of ASK1 (ASK1-Delta N) in an adenoviral vector in four neuroblastoma cell lines, two murine, C1300 and NXS2, and two human, SH-SY5Y and IMR-32. Already after 24 h upon infection, C1300 and SH-SY5Y cells arrested in growth when judged by [(3)H]thymidine incorporation, and the majority of the cells demonstrated apoptotic appearance, which was confirmed by DNA-laddering in gel electrophoresis. In contrast, NXS2 and IMR-32 cell lines remained unaffected. Immunoblotting revealed strongly phosphorylated p38 MAPK accompanied by weakly phosphorylated JNK in C1300 and SH-SY5Y, whereas none of these kinases were activated by adenoviruses expressing the kinase negative ASK1 mutant or beta-galactosidase. There was no expression of phosphorylated kinases in IMR-32 cells, but NXS2 showed a faint band of phosphorylated p38 MAPK. Addition of the p38 MAPK specific inhibitor, SB203580, protected C1300 and SH-SY5Y cells from apoptosis induced by ASK1-Delta N. The anti-neoplastic agent, paclitaxel, activates ASK1 and JNK, and promotes the in vitro assembly of stable microtubules. Addition of 10 nM paclitaxel sensitised the NXS2 cell line to ASK1-induced cell death. Our results indicate that ASK1 induces apoptosis in neuroblastoma cells mainly via the p38 MAPK pathway, and resistant neuroblastoma cells can be sensitised to ASK1 by paclitaxel.
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PMID:ASK1 resistant neuroblastoma is deficient in activation of p38 kinase. 1159 1

High-dose chemotherapy (HDCT) and autologous bone marrow transplantation (BMT) is frequently used to treat patients with metastatic cancer including breast cancer and neuroblastoma. However, the bone marrow of such patients is often contaminated with tumor cells. Recently, we have found that a recombinant adenovirus vector that contains a bcl-x, minigene (a dominant negative inhibitor of the bcl-2 family), called the bcl-x(s) adenovirus, is lethal to cancer cells derived from epithelial tissues, but not to normal human hematopoietic cells. To determine the mechanism, by which this virus spares normal hematopoietic cells, we isolated normal mouse hematopoietic stem cells and infected them with an adenovirus that contains a beta-galactosidase minigene. Such cells do not express beta-galactosidase, indicating that hematopoietic stem cells do not express transgene encoded by adenovirus vectors based upon the RSV-AD5 vector system. When breast cancer cells mixed with hematopoietic cells were infected with the bcl-x(s) adenovirus, cancer cells were selectively killed by the suicide adenoviruses. Hematopoietic cells exposed to the suicide vectors were able to reconstitute the bone marrow of mice exposed to lethal doses of y-irradiation. These studies suggest that adenovirus suicide vectors may provide a simple and effective method to selectively eliminate cancer cells derived from epithelial tissue that contaminate bone marrow to be used for autologous BMT. We therefore propose to initiate a phase I clinical trial to test the safety of this virus in women with breast cancer undergoing high does chemotherapy and autologous BMT.
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PMID:Clinical protocol. Purging of autologous stem cell sources with bcl-x(s) adenovirus for women undergoing high-dose chemotherapy for stage IV breast carcinoma. 1172 34

Vascular endothelial growth factor (VEGF) is known to play a predominant role in tumor angiogenesis and metastasis formation that is mediated by its interactions with two tyrosine kinase receptors, VEGFRI (Flt-1) and VEGFRII (KDR). Inhibition of VEGF-dependent events in tumor tissues is known to enhance apoptosis and to suppress tumor growth. A novel peptide, SP5.2, which selectively binds Flt-1 and inhibits a broad range of VEGF-mediated events, was identified using a phage-display library screening. The fluorescein-labeled SP5.2 specifically bound to VEGF-stimulated primary human cerebral endothelial cells (HCECs), whereas non-stimulated HCECs, as well as human neuroblastoma cells (ShyY) did not show any interaction with the peptide. SP5.2 prevented proliferation of cultured primary human umbilical vein endothelial cells induced by recombinant human VEGF165 with an IC50 of 5 microm. SP5.2 was also shown to antagonize VEGF- and PLGF-induced, but not basic fibroblast growth factor-induced proliferation of HCECs. In contrast to "scrambled" peptide, SP5.2 was also found to selectively inhibit VEGF-stimulated migration of HCECs. The in vitro analysis of antiangiogenic activity of SP5.2 using a capillary-like tube formation assay showed that VEGF-induced angiogenesis of HCECs grown on Matrigel was completely inhibited in the presence of 10 microm SP5.2. Further studies demonstrated that SP5.2 prevented VEGF-induced permeability increase in HCECs monolayers. To explore whether SP5.2 can be used as a targeting agent, chemical and recombinant conjugates of SP5.2 with reporter proteins (peroxidase and beta-galactosidase) were produced. The resulting products showed significant increases (200-fold for SP5.2-beta-gal and 400-fold for SP5.2-peroxidase) in binding affinity to recombinant Flt-1 compared with the original synthetic SP5.2, suggesting that conjugate with therapeutic activity in nanomolar range could potentially be developed based on SP5.2 structure.
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PMID:A vascular endothelial growth factor high affinity receptor 1-specific peptide with antiangiogenic activity identified using a phage display peptide library. 1295 24

Human neuroblastoma GOTO cell lines were established that stably express recombinant human lysosomal protective protein/cathepsin A (PPCA) cDNA by transfection. Intracellular cathepsin A (acid serine carboxypeptidase) activity increased four-fold compared with in those of the parent and mock-transfected cell lines. The immunoreactive 54 kDa precursor/zymogen and mature 32/20 kDa two-chain forms were produced in the cells. The amount of the latter form expressed in the GOTO cells was significantly larger than those in the PPCA-overexpressing CHO cell lines previously established. The intracellular proteins showed a typical lysosomal granular distribution and the glycosylated 54 kDa precursor was secreted into the culture medium without the addition of an alkalizing agent. The PPCA-overexpressing cell lines also retained the ability to differentiate bi-directionally as well as the parent cells; into neuronal cells on induction by dibutyryl cAMP in serum-free medium and into Schwannian cells on induction by bromodeoxyuridine. During the course of differentiation into neuronal and Schwannian cells, the intracellular cathepsin A activity further increased two and five times, respectively, which was associated with an increase in the expression of the 32/20 kDa two-chain form. The glycosylated precursor proteins were taken up via the mannose 6-phosphate receptors, and the cathepsin A, alpha-neuraminidase and beta-galactosidase (beta-Gal) activities deficient in the fibroblasts derived from a patient with PPCA deficiency (galactosialidosis) were restored. These results suggest that the bi-directional differentiation of GOTO cell lines stably expressing the recombinant human PPCA gene could be a model system for analyzing the functions of PPCA in peripheral neuronal cells and Schwannian cells as well as the recombinant PPCA could be a useful source for enzyme replacement therapy (ERT) for galactosialidosis patients.
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PMID:Expression of lysosomal protective protein/cathepsin A in a stably transformed human neuroblastoma cell line during bi-directional differentiation into neuronal and Schwannian cells. 1468 10

There has recently been increasing interest in the development of radioprobes that specifically target proteins transcribed from expression of reporter genes of interest. The purpose of this study was to develop a radioprobe that targets one of the most widely used reporter genes, the bacterial lacZ gene. We synthesised and purified radioiodine-labelled phenylethyl-beta- d-thiogalactopyranoside (PETG), a competitive inhibitor specific against Escherichia coli beta-galactosidase. We showed that [(125)I]iodo-PETG specifically binds to beta-galactosidase as verified by column chromatography and polyacrylamide gel electrophoresis after incubation of radiotracer with the protein. We also showed through enzyme kinetic studies that iodo-PETG retains inhibitory action against beta-galactosidase activity. COS-7 cells infected with a recombinant adenovirus expressing the lacZ gene had viral titre-dependent enhancements in [(125)I]iodo-PETG uptake ( r(2)=0.897; P=0.001), which reached up to 642.5%+/-16.7% of control levels ( P<0.00001). Moreover, the level of uptake was highly correlated to luminescent measurements of beta-galactosidase activity ( r(2)=0.878; P<0.0001). These results confirm that radioiodine-labelled PETG specifically targets beta-galactosidase and that its uptake rates faithfully reflect levels of expression of the lacZ reporter gene. Further investigations were performed in nude mice bearing human neuroblastoma tumours transferred with the lacZ gene. Compared with control tumours, lacZ-expressing tumours were slightly better visualised on [(123)I]iodo-PETG images and had a modest increase in tumour to muscle count ratio (2.6+/-0.2 vs 1.9+/-0.1, P<0.05). The present results provide proof-of-principle for the potential of radiolabelled inhibitors as promising radiotracers to monitor lacZ gene expression levels. Future modifications to improve cell permeability should enhance in vivo contrast levels and may allow the use of radiolabelled beta-galactosidase inhibitors for non-invasive monitoring of lacZ gene expression.
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PMID:Targeting of lacZ reporter gene expression with radioiodine-labelled phenylethyl-beta- d-thiogalactopyranoside. 1474 16

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