Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The toxic effects of two metabolic inhibitors, dinitrophenol and iodoacetic acid, were compared. Mouse neuroblastoma cell cultures (Neuro-2a) were exposed to different concentrations of the toxic compounds for 24, 48 and 72 h to study basal toxicity effects (cell proliferation by quantification of total protein content (PR) and relative neutral red uptake (RNRU) by lysosomes). The following biochemical indicators assessed in the in vitro test system were: 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 (AChE) activity. The effects of the two metabolic inhibitors on the various indicators differed. Iodoacetic acid was found to be far more toxic than dinitrophenol to neuroblastoma cell proliferation at 24 h exposure. Though 2,4-dinitrophenol and iodoacetic acid both inhibited cell proliferation of the neuroblastoma cells, their effects on the other endpoints were opposite. Dinitrophenol was a general activator of the metabolism, particularly affecting lysosomal function. Iodoacetic acid did not significantly alter general metabolism, but considerably modified lysosomal function and AChE activity. The modification of lysosomal function of Neuro-2a cells by the two compounds was quite different: dinitrophenol increased RNRU and GAL activity, and iodoacetic acid decreased both parameters.
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PMID:Comparative effects of the metabolic inhibitors 2,4-dinitrophenol and iodoacetate on mouse neuroblastoma cells in vitro. 865 53

The physiologically active metabolite of vitamin D3, 1,25-dihydroxycholecalciferol (D3), plays an important role in embryonic development and cell differentiation. Previously, we have demonstrated that D3 significantly induces differentiation and inhibits growth of LA-N-5 human neuroblastoma cells at concentrations of 24 nm and higher. In this study, we compared two D3 analogs, 20-epi-22oxa-25a,26a,27a-tri-homo-1,25-D3 (KH 1060) and 1,25-dihydroxy-22,24-diene, 24,26,27-trihomo (EB 1089), with D3 with respect to their effects on differentiation and growth inhibition. We report an inhibition of growth by 45-55% in cells treated with 0.24 nm EB 1089 and 0.24 nM KH 1060, similar to that seen in cells treated with 24 nM D3. At these concentrations, both EB 1089 and KH 1060 stimulate the differentiation of LA-N-5 neuroblastoma cells as shown by increased neurite outgrowth, decreased N-myc expression and decreased invasiveness in vitro. An increase in acetylcholinesterase activity, a functional measure of differentiation, was also exhibited. Previous reports have shown that treatment doses needed to achieve 24 nM serum concentrations of D3 in patients would result in hypercalcemia. EB 1089 and KH 1060 can cause the same in vitro effects on LA-N-5 human neuroblastoma cells at 1/100 of the concentration required of D3. These data suggest a potential clinical efficacy of EB 1089 and KH 1060 as biological response modifiers.
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PMID:Vitamin D3 analogs inhibit growth and induce differentiation in LA-N-5 human neuroblastoma cells. 867 78

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (beta APP). Soluble derivatives of beta APP generated by the proteolytic processing of full-length beta APP are normally secreted into the conditioned medium of cultured cells. Here we have investigated the possibility that the processing of beta APP can be regulated by the cholinesterase inhibitors physostigmine and tacrine. Both drugs mildly improve cognitive functions in some patients with AD. We analyzed the level of beta APP in glial, neuroblastoma, and pheochromocytoma cells by immunoblotting cell lysates and conditioned media using a monoclonal antibody, MAb22C11. The levels of soluble beta APP derivatives normally present in conditioned media were severely inhibited by treating cells with tacrine but not with physostigmine. Whereas the treatment of cells with tacrine resulted in a small decrease in the intracellular levels of beta APP, treating cells with physostigmine resulted in a slight increase in the intracellular levels of beta APP compared to untreated cells. The effect of tacrine on the secretion of beta APP was not affected by cotreating cells with muscarinic agents, staurosporine, or the calcium ionophore. Our results suggest that a decrease in the secretion of beta APP by tacrine did not depend on its anticholinesterase activity and that tacrine operates via a noncholinergic mechanism.
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PMID:Differential effect of tacrine and physostigmine on the secretion of the beta-amyloid precursor protein in cell lines. 883 81

This study addresses the developmental regulation of amyloid precursor protein (APP) fragments comprising the amyloid-beta peptide (AP) and the amyloid-promoting factor acetylcholinesterase (AChE) in a mouse neuronal cell line (Neuro-2a). Results indicate that a 35-kDa amyloidogenic fragment of APP and the major molecular forms of AChE (G1 and G4) in Neuro-2a cells significantly increase with increasing levels of cell confluence. The foregoing molecules undergo further increases when neuroblastoma cells differentiate in the presence of dibutyryl cAMP. In contrast, a 17-kDa fragment of APP and butyrylcholinesterase were not affected by cell confluence or differentiation. These findings are the first to indicate that a selective Abeta-containing fragment of APP is subject to developmental regulation. Moreover, our data show that the 35-kDa fragment and AChE forms respond in parallel to the same developmental stimuli, i.e., cell confluence and differentiation. This points to the existence of a functional relationship between both molecules, a notion that is consistent with the potential role that has been ascribed to AChE in both APP processing and the formation of amyloid deposits in Alzheimer's brains.
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PMID:Amyloid precursor protein fragment and acetylcholinesterase increase with cell confluence and differentiation in a neuronal cell line. 894 Feb 53

Gangliosides on the external side of the plasma membrane are important modulators of cellular functions. In previous work we had found that in cultured human SK-N-MC neuroblastoma cells a cell surface sialidase activity specifically cleaved terminal sialic acids from gangliosides, leading to a shift from higher sialylated species to GM1 and a decrease of GM3. To further elucidate the function of the enzyme, we have now examined the consequences of ganglioside sialidase inhibition. When present in the culture medium, the ganglioside sialidase inhibitors 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NeuAc2en), heparin, and heparan sulfate caused dramatic changes in cell behavior. Thus, the inhibitors uniformly led to a complete release from contact inhibition of growth, and to the loss of the differentiation markers neuron-specific enolase and neurofilaments, and a decrease of cyclic AMP. In presence of NeuAc2en, cells that normally were spread out evenly and were firmly attached, appeared smaller, rounded, and only loosely adherent to the culture vessel. Exogenous addition of vibrio cholerae sialidase mimicked the action of the plasma membrane ganglioside sialidase by retarding cell proliferation and increasing intracellular acetylcholinesterase. That the ganglioside sialidase inhibitors in the culture medium indeed affected solely the cell surface enzyme and not also a lysosomal sialidase, was demonstrated in an experiment where the desialylation of exogenously added radioactive gangliosides was determined in absence and presence of NeuAc2en and NH4Cl, an inhibitor of lysosomal function. Taken together, our results suggest that the ganglioside sialidase on the surface of SK-N-MC cells is responsible for growth control and differentiation in this neuronal cell line.
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PMID:Effects of cell surface ganglioside sialidase inhibition on growth control and differentiation of human neuroblastoma cells. 917 66

The differential inhibition of the target esterases acetylcholinesterase (AChE) and neuropathy target esterase (NTE, neurotoxic esterase) by organophosphorus compounds (OPs) is followed by distinct neurological consequences in exposed subjects. The present study demonstrates that neuroblastoma cell lines (human SH-SY5Y and murine NB41A3) can be used to differentiate between neuropathic OPs (i.e., those inhibiting NTE and causing organophosphorus-induced delayed neuropathy) and acutely neurotoxic OPs (i.e., those highly capable of inhibiting AChE). In these experiments, concentration-response data indicated that the capability to inhibit AChE was over 100x greater than the capability to inhibit NTE for acutely toxic, nonneuropathic OPs (e.g., paraoxon and malaoxon) in both cell lines. Inhibition of AChE was greater than inhibition of NTE, without overlap of the concentration-response curves, for OPs which are more likely to cause acute, rather than delayed, neurotoxic effects in vivo (e.g., chlorpyrifos-oxon, dichlorvos, and trichlorfon). In contrast, concentrations inhibiting AChE and NTE overlapped for neuropathy-causing OPs. For example, apparent IC50 values for NTE inhibition were less than 9.6-fold the apparent IC50 values for AChE inhibition when cells were exposed to the neuropathy-inducing OPs diisopropyl phosphorofluoridate, cyclic tolyl saligenin phosphate, phenyl saligenin phosphate, mipafox, dibutyl dichlorovinyl phosphate, and di-octyl-dichlorovinyl phosphate. In all cases, esterase inhibition occurred at lower concentrations than those needed for cytoxicity. These results suggest that either mouse or human neuroblastoma cell lines can be considered useful in vitro models to distinguish esterase-inhibiting OP neurotoxicants.
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PMID:Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. 926 5

Analysis of the molecular factors that control cellular differentiation in mammalian embryos is difficult due to the small amount of material available from embryos and their inaccessibility during gestation. One way to circumvent these limitations is to use model systems that allow the study of differentiation in vitro. In this study we have characterized the response of a human neuroblastoma cell line, LA-N-5, to the differentiation-inducing agent, all-trans retinoic acid (RA) using 23 markers that are characteristic of neural crest cells and some of their derivatives. Following induction with RA, the neural crest-like LA-N-5 cells undergo differentiation into cholinergic neurons with increased expression of a variety of neural-specific markers including neurofilaments, growth associated protein-43, tetanus toxin binding sites, receptors for neurotrophic factors, neuropeptides, choline acetyl transferase, vesicular acetylcholine transporter, and acetylcholinesterase with a concomitant decrease in the expression of non-neuronal markers. These results provide the basis for the use of retinoic acid-induced differentiation of LA-N-5 cells as a model system to study molecular events associated with the differentiation of cholinergic neurons.
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PMID:Characterization of the cholinergic neuronal differentiation of the human neuroblastoma cell line LA-N-5 after treatment with retinoic acid. 929 34

One of the main characteristics of Alzheimer's disease (AD) is the cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). The majority of beta APP is processed by either a secretory of lysosomal/endosomal pathway. Carboxyl-truncated soluble derivatives of beta APP (sAPP) are generated by the proteolytic processing of full-length beta APP by either alpha- or beta-secretase enzyme. Our objective is to determine whether the processing of beta APP can be regulated by cholinesterase inhibitors, some of which were shown to produce a moderate improvement in memory and cognitive functions in patients with Alzheimer's disease. Here we have analyzed the levels of sAPP derivatives in cultured cells treated with different drugs by immunoblotting samples of conditioned media. The immunoreactive protein bands were developed by probing with the monoclonal antibody 22C11. Treating neuroblastoma, pheochromocytoma and fibroblast cells with high dose of either 3,4-diaminopyridine, metrifonate, or physostigmine did not inhibit the secretion of sAPP. Treating glioblastoma with either 3,4-diaminopyridine or metrifonate showed an increase in secretion of sAPP. However, treatment of cells with tacrine reduced release of sAPP in conditioned media of cell lines studied. The difference in action of metrifonate, physostigmine, and tacrine on beta APP is independent of their anticholinesterase activities. Our results suggests that noncatalytic functions of cholinesterase inhibitors can be utilized to alter the metabolism of beta APP, which might in turn affect the process of deposition of A beta, a key component of the cerebrovascular amyloid detected in AD.
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PMID:Effects of cholinesterase inhibitors on the secretion of beta-amyloid precursor protein in cell cultures. 932 15

Agrin is a synapse-organizing molecule that mediates the nerve-induced aggregation of acetylcholine receptors (AChRs) and other postsynaptic components at the developing and regenerating vertebrate neuromuscular junctions. At the neuromuscular junction, three different cell types can express agrin, i.e., neuron, muscle, and Schwann cell. Several lines of evidence suggested that neuron-derived agrin is the AChR-aggregating factor, but the possible roles of muscle-derived agrin in the formation of AChR aggregate are not known. By using the recombinant DNA method, a clonal stable C2C12 cell line transfected with antisense agrin cDNA was created. RNA dot blot and western blot analysis indicated that the expression of agrin in the transfected cell was abolished by DNA transfection. When the agrin-deficient C2C12 cells were induced to form myotubes and subsequently cocultured with agrin cDNA transfected fibroblasts, AChR aggregates were formed in the cocultures. In addition, acetylcholinesterase (AChE) aggregates in agrin-deficient myotubes were also induced by exogenous agrin and the AChE aggregates were colocalized with the AChR aggregates. The agrin-deficient myotubes could also respond to neuron-induced AChR aggregation after coculturing with neuroblastoma cells. Thus, the agrin-deficient myotubes retain their ability to exhibit the agrin- or neuron-induced AChR aggregation. This result suggests that the formation of postsynaptic specializations during development and regeneration is mediated by neuron-derived agrin but not the agrin from muscle.
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PMID:Agrin-deficient myotube retains its acetylcholine receptor aggregation ability when challenged with agrin. 937 89

Although muscular activity has been demonstrated to regulate the expression of acetylcholinesterase (AChE) in cultured myotubes, the exact role of the presynaptic terminus in regulating AChE expression at the neuromuscular junctions is not known. A chimeric co-culture of neuroblastoma x glioma hybrid NG108-15 cells with chick myotubes was established. By using chick-specific anti-AChE antibody, a protein of approximately 105 kDa in size corresponding to chick AChE catalytic subunit was revealed by Western blot analysis from the extracts of neuron-muscle co-cultures. In the co-cultures, NG108-15 cells induced the up regulation of muscle AChE expression by approximately 2.5-fold, while the control protein, chick muscle alpha-actinin at approximately 100 kDa, remained relatively unchanged. The NG108-15 cell-induced muscle AChE expression in the co-cultures was persistent when the muscular activity was blocked by alpha-bungarotoxin. In order to determine the AChE-inducing activity derived from NG108-15 cells, the cultured chick myotubes were treated with either conditioned medium of NG108-15 cells or its cell lysate. However, the muscle AChE, both in protein and activity levels, remained relatively unchanged. Our finding suggests that an AChE-inducing factor(s) is derived from the neuroblastoma cells in the co-cultures, but that may require the nerve-muscle contacts in culture.
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PMID:NG108-15 cells induce the expression of muscular acetylcholinesterase when co-cultured with myotubes. 940 63


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