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)

Choline acetyltransferase (Acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6, abbreviated ChAT), the biosynthetic enzyme for acetylcholine and acetylcholinesterase (EC 3.1.1.7, abbreviated AChE) are expressed in a human cholinergic neuroblastoma cell line, MC-IXC. We have shown that ChAT activity can be regulated in culture by retinoic acid, an active metabolite of vitamin A, and by sodium butyrate, an organic fatty acid. Optimal concentrations of these agents produce 4.3-fold and 1.6-fold increases in ChAT activity, respectively. The effects of retinoic acid are statistically significant after 24 h, whereas for sodium butyrate significant differences are seen only after 48 h. Since retinoic acid stimulation of ChAT activity was reversed only by trypsin treatment and not by removal of retinoic acid from the medium, this suggests that this agent may be acting at the level of the cell surface. Other differentiating conditions, such as culture in serum-free medium or addition of 1-2% dimethylsulfoxide did not increase ChAT activity. Acetylcholinesterase activity was shown to increase only in the presence of sodium butyrate, suggesting that retinoic acid and sodium butyrate may be acting via different pathways. Retinoic acid and sodium butyrate both seem to be permissive rather than instructive in regulating ChAT activity in that they are unable to induce ChAT expression de novo in cell lines which do not already express ChAT activity.
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PMID:Stimulation of choline acetyltransferase activity by retinoic acid and sodium butyrate in a cultured human neuroblastoma. 292 23

In our previous report we have shown that the enzyme choline acetyltransferase (ChAT), responsible for the synthesis of the neurotransmitter acetylcholine, can be regulated in response to treatment by either retinoic acid or sodium butyrate. These responses were dose and time dependent, but the mechanism by which these agents were acting was not understood. We now report the results of studies aimed at elucidating the level at which both sodium butyrate and retinoic acid are able to increase ChAT activity. The effects of these agents on macromolecular synthesis appeared to be limited to small but statistically significant increases in the rate of RNA synthesis. However, inhibition of DNA, RNA and protein synthesis in these cells had no effect on the stimulation of ChAT activity by either sodium butyrate or retinoic acid. Several experiments appeared to rule out a role for cyclic AMP or protein kinase C in the regulation of ChAT activity, even though retinoic acid treatment could increase endogenous levels of cyclic AMP 3- to 4-fold over the time course of ChAT activity stimulation. Experiments performed to determine kinetic parameters of this enzyme demonstrated changes only in the Vmax, but not the Km of ChAT, suggesting that the affinity of enzyme for either of its substrates was not responsible for the increase in specific activity. Taken together, this evidence suggests that the activation of choline acetyltransferase in this human neuroblastoma cell line occurs at the post-translational level.
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PMID:Mechanism of activation of choline acetyltransferase in a human neuroblastoma cell line. 292 24

We investigated the effects of a number of experimental perturbations on choline acetyltransferase (ChAT) in a cholinergic mouse neuroblastoma cell line (S-20Y). ChAT specific activity increased by 4.5-fold during growth, suggesting that enzyme activity is dependent on increased cell density. This was confirmed by assessing enzyme activity at differential initial seeding densities. ChAT activity was also markedly enhanced by 1 mM dibutyryl cyclic-3',5'-AMP (dBcAMP), an effect that was blocked by cycloheximide. Confirmation of the dBcAMP effect was achieved with forskolin, a compound known to enhance intracellular cyclic AMP; forskolin (100 microM) caused a significant increase in ChAT activity. After a 20-h latent interval ChAT activity was also enhanced significantly by cytosine arabinoside. The common element in these diverse effects on ChAT activity may be cessation of cell division, although cell-cell interactions at the level of the cell membrane may also be important in the control of ChAT in S-20Y.
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PMID:Effects of cell division, cell density, and cyclic nucleotides on choline acetyltransferase activity in a cholinergic neuroblastoma cell line (S-20Y). 300 94

This study was designed to establish an in vitro model with biochemical and morphological similarities to the human neurodegenerative disease GM1 gangliosidosis. Utilizing a specific inactivator of the lysosomal enzyme GM1-ganglioside beta-galactosidase (beta-D-galactopyranosylmethyl-p-nitrophenyltriazene [beta-GalMNT]) and neuroblastoma X glioma hybrid cells (NG108-15), we suppressed beta-galactosidase activity for up to 72 hours. Coincidental with suppression of this enzyme to levels less than 1% of control, we found up to a nine-fold accumulation of its substrate, the GM1-ganglioside, and the ultrastructural appearance of membranous cytoplasmic bodies. beta-GalMNT treatment suppressed growth but had little effect on the specific activity of choline acetyltransferase, lactate dehydrogenase, or other lysosomal enzymes including galactosylceramidase. This model should permit studies of the neurophysiological effects of increased ganglioside accumulation and their reversibility.
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PMID:Inactivation of GM1-ganglioside beta-galactosidase by a specific inhibitor: a model for ganglioside storage disease. 303 98

The effects of anticonvulsants on markers of growth, intracellular enzymes, and synaptic functions were evaluated using a rapidly dividing cholinergic neuroblastoma x glioma hybrid cell-line (NG108-15). Cell cultures were exposed for 4 days to phenobarbital, phenytoin, carbamazepine, or valproic acid. Anticonvulsant concentrations added to the media were selected to produce free levels in the cell media that were equivalent to free levels in humans ranging from therapeutic to very toxic. Free levels of anticonvulsants in the toxic range affected cell number, protein content, and neurochemical markers. However, only valproic acid and phenytoin reduced cell growth at therapeutic free drug concentrations. Valproic acid was the only medication to act as a differentiating agent, significantly increasing the activity of choline acetyltransferase, beta-galactosidase, and muscarinic cholinergic receptor binding. These results emphasize the importance of performing drug studies at appropriate free drug concentrations and suggest that valproic acid differs from other commonly prescribed anticonvulsants by having both a growth-suppressing and a differentiating effect.
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PMID:Effects of anticonvulsants on cell growth and enzymatic and receptor binding activity in a neuroblastoma x glioma hybrid cell culture. 310 72

Six new cell lines have been established from human neuroblastomas. Cell line SMS-KAN, from primary tumor before therapy, and line SMS-KANR, from bone marrow after chemotherapy and radiotherapy, were established from the same patient. Cell lines SMS-KCN (from primary tumor before any therapy) and SMS-KCNR (from bone marrow after chemotherapy) were established from another patient. Two other lines (SMS-MSN and SMS-SAN) were established from different patients before any therapy was given. Cell lines established from recurrent disease after chemotherapy (SMS-KANR and SMS-KCNR) had significantly shorter doubling times and increased plating efficiencies compared to those of cell lines derived from the same patient before chemotherapy (SMS-KAN and SMS-KCN). All cell lines contained tyrosine hydroxylase, aromatic L-amino acid decarboxylase, and dopamine-beta-hydroxylase. Measurable amounts of choline acetyltransferase were also detected in SMS-KAN and SMS-KANR. Karyotype analysis showed all cell lines except SMS-MSN to be pseudodiploid with modal numbers of 46 and deletions of the short arm of chromosome 1; SMS-MSN had a modal number of 57-58 chromosomes. All cell lines had double-minute chromosomes, except SMS-KANR, which had abnormally banding regions. These new cell lines provide in vitro models of neuroblastoma suitable for the study of differences in neuroblastoma cell populations before chemotherapy as compared to the cell populations that proliferate after therapy.
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PMID:Characterization of human neuroblastoma cell lines established before and after therapy. 345 56

The specific binding of the muscarinic ligand [3H](-)quinuclidinyl benzilate [( 3H]QNB) to cell membranes of human SH-SY5Y neuroblastoma cells was studied. Saturation isotherms yielded a Kd = 0.28 +/- 0.06 nM and a Bmax of 337 +/- 47 pmol/g protein. Pirenzepine inhibited [3H]QNB binding; inhibition data showed best fit to a 2-site binding model revealing both a high affinity pirenzepine site (34%, KH = 10 nM) and a low affinity site (66%, KL = 1 microM). These results indicate that muscarinic receptors on SH-SY5Y cells may be subclassified as M1/M2 subtypes. Morphological and biochemical differentiation of these cells after treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or retinoic acid (RA) resulted in a decrease and an increase in the number of muscarinic binding sites, respectively. Furthermore, TPA- and RA-treated cells showed a significant increase in acetylcholinesterase activity compared with non-treated cells. However, only RA-treated cells showed significant increase in choline acetyltransferase activity compared to non-treated cells. These findings demonstrate that TPA and RA can regulate both the number of muscarinic receptors and the acetylcholinesterase activity in human SH-SY5Y neuroblastoma cells.
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PMID:Muscarinic receptors in human SH-SY5Y neuroblastoma cell line: regulation by phorbol ester and retinoic acid-induced differentiation. 360 14

The present experiments were aimed to determine the extent to which differentiated neuroblastoma cells may serve as a donor source for neural transplantation studies. Rodent-derived C1300 and human-derived LA-N-2 cells stained positively for choline acetyltransferase in vitro whether left untreated or rendered amitotic with mitomycin C/bromodeoxyuridine (Brdu) treatment. The two cell lines in both mitotic and differentiated states were subsequently transplanted into the hippocampus of rats that had previously undergone posterodorsal medial septal lesions. The undifferentiated cells continued to proliferate and formed large masses in the host brain within 7 days after implantation. When differentiated with mitomycin C/Brdu, the cells were autoradiographically visualized in large numbers 7 days following transplantation. Fewer cells were observed at the 30 and 120 test intervals. At the later time points the C1300 cells were found primarily within the host parenchyma while the LA-N-2 cells were found predominantly in the subependymal region below the hippocampus. These differentiated cells were also able to attenuate the cognitive dysfunction produced by medial septal lesions. However, an exact neurochemical mechanism cannot presently be ascribed to this effect since the cells failed to stain for choline acetyltransferase in vivo. At no time did differentiated cell grafts appear to revert to a neoplastic state nor was a significant immunological response observed. These findings, in concordance with other studies by our group, suggest that neuroblastoma cell lines may prove to be a practical source of donor tissue for neural transplants.
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PMID:Neuroblastoma cells in neural transplants: a neuroanatomical and behavioral analysis. 362 Sep 80

A 6-day in vitro growth-inhibition assay was used to determine relative sensitivity of six human neuroblastoma cell lines to three classes of cancer chemotherapeutic agents: antimetabolites (methotrexate, methasquin, and cytarabine); antimitotics (vincristine, vinblastine, vindesine, colchicine, and demecolcine); and antibiotics (dactinomycin and doxorubicin). Human fibroblast lines served as a reference standard. Whereas response to antimetabolites by four of five neuroblastoma lines tested was similar to that of fibroblasts, SK-N-MC cells were significantly more sensitive (fivefold to 16-fold) to the three drugs. Human neuroblastoma cell lines were also differentially sensitive to antimitotics, especially to vincristine. In particular, SK-N-MC, IMR-32, and LA-N-2 cells were threefold to 17-fold more sensitive to this drug than were the SK-N-SH and SK-N-BE(2) lines. With the exception of SK-N-SH, all of the human neuroblastoma lines were considerably more sensitive to vincristine than were human fibroblasts. The same three highly vincristine-responsive lines were also significantly more sensitive to the other alkaloidal drugs as compared to fibroblasts. However, human neuroblastoma and fibroblastic cells responded similarly to the two antibiotics. The only cellular attribute consistently correlated with greater sensitivity to the antimitotics among the six cell lines tested was expression of the neurotransmitter biosynthetic enzyme choline acetyltransferase. A differential response to the vinca alkaloids was also exhibited by clonal sublines of SK-N-SH. One subpopulation (SH-EP) expressing a nonneuronal, substrate-adherent, variant phenotype was at least fourfold to eightfold more drug sensitive than its neuroblastic counterpart (SH-SY5Y) or the parental SK-N-SH population. In addition to confirming reports of clinical efficacy of the various classes of agents, these data have demonstrated a variation in response possibly related to type or degree of neuronal differentiation and emphasize the importance of understanding the phenotypic diversity commonly observed in neuroblastoma.
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PMID:Differential drug sensitivity of human neuroblastoma cells. 373 Nov 52

Thyroid hormone (T3) has a multiplicity of effects on the developing nervous system. We have investigated T3 action using a cholinergic neuroblastoma cell line (S-20Y) as a model. S-20Y contains a nuclear receptor for T3 with binding properties similar to those of other T3 target tissues. In addition, these cells can carry out 5'-deiodination, which is necessary to produce active thyroid hormone in vivo. The enzyme involved in this process appears to be a type I deiodinase, based on its reaction kinetics and its susceptibility to inhibition by propylthiouracil. S-20Y cells maintained in T3-depleted medium showed decreased choline acetyltransferase (ChAT) activity. ChAT activity was restored to the control level in a dose-dependent manner by T3 repletion. Neither cell density nor viability was influenced by the hypothyroid state. The presence of a T3 receptor and the enzyme activity for T3 production, together with an effect of T3 on ChAT activity, demonstrate that S-20Y cells are a target for T3 action and suggest that these cells represent an excellent model system for studies of T3 effects on nervous tissues.
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PMID:Thyroid hormone actions on a cholinergic neuroblastoma cell line (S-20Y). 376 Aug 76


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