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)

Rat models of Parkinson's disease typically employ a rapid nigral injection of 6-hydroxydopamine (6-OHDA) to produce a near-complete loss of nigrostriatal dopamine neurons, and thus, model end stage disease. The present report describes the use of a continuous, low dose infusion of 6-OHDA into the striatum which produces a terminal axotomy of nigrostriatal dopamine neurons and protracted behavioral response. A solution of 6-OHDA in 0.4% ascorbate, delivered at 37 degrees C from osmotic minipumps, was stable for 8 days as determined by its retained toxicity to a dopaminergic neuroblastoma cell line. The continuous infusion of 0.2 mu g 6-OHDA per h did not affect the striatal uptake of [3H]%GABA, [3H]choline, or [3H]glutamate but reduced [3H]dopamine uptake by 55% within 1.5 days after the start of the infusion. The striatal infusion of 6-OHDA produced a dose-dependent reduction of striatal dopamine and DOPAC levels but did not alter HVA, 5-HT, or 5-HIAA. An increase in amphetamine-induced ipsiversive rotations occurred within 1.5 days after the acute striatal injection of 20 mu g or 30 mu g of 6-OHDA but required 4 days to develop with the continuous 6-OHDA infusion. The topography of the lesion mapped by [3H]mazindol binding showed that, beginning by 1.5 days, a diffuse depletion of terminals encompassed much of the striatum in the 30 mu g acute injection group, whereas in the continuously infused rats, the lesion was apparent only by 4 days and was restricted to a smaller and more completely lesioned area. Unlike acutely lesioned animals, continuously infused rats revealed no obvious loss of dopamine neurons in the pars compacta by 5 weeks after 6-OHDA. The continuous striatal infusion of 6-OHDA can produce a topographically limited terminal axotomy of dopamine neurons and a protracted behavioral impairment.
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PMID:A continuous striatal infusion of 6-hydroxydopamine produces a terminal axotomy and delayed behavioral effects. 883 64

The kinetics of ascorbate (AscH ) and epinephrine (EP) oxidation in the presence of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (UQ) were studied in 0.05 M phosphate buffer, pH 7.4, at 37 degrees C by using a Clark electrode and ESR techniques. UQ at nanomolar concentrations displayed a pronounced catalytic effect on AscH oxidation which exceeded that of all reported organic catalysts tested in this system. The process was accompanied by the intensive oxygen consumption and increase in the steady-state concentration of the ascorbyl radical Asc.-. The rate of oxygen consumption (R[OX]) was maximal at the moment of reagent mixing ((R[OX]0) and then reduced over a few minutes until a steady-state level ((R[OX])SS) was achieved. (R[OX])0 was found to be proportional to [UQ][AscH-] without regard to the concentrations of the individual reagents; (R[OX])SS was directly related to [UQ] at a given concentration of AscH-. The difference between (R[OX])0 and (R[OX])SS decreased as [AscH-] decreased. The presence of a lipid phase (sodium dodecylsulphate micelles) only moderately decreased UQ activity as a catalyst of AscH- oxidation. Adding micromolar concentrations of UQ induced the acceleration of EP autoxidation. The capability of UQ to catalyze the oxidation of EP exceeded by approximately 25 times that of adrenochrome, a quinoid product of EP oxidation. These catalytic properties of UQ allowed us to predict its pronounced cytotoxicity, especially in the presence of AscH- and to cells of the sympathetic nervous system which are rich in catecholamines. This possibility was confirmed by experiments with human neuroblastoma cells in culture. The capability of UQ to injure neuroblastoma cell line SK-N-SH exceeded that of well-known neurotoxic agents 6-hydroxydopamine and menadione.
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PMID:Ubiquinone-0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone) as effective catalyzer of ascorbate and epinephrine oxidation and damager of neuroblastoma cells. 941 34

Buthionine sulphoximine (BSO) selectively inhibits glutathione (GSH) synthesis and may enhance the antineuroblastoma activity of melphalan (L-PAM). We determined the cytotoxicity of BSO (dose range 0-1000 microM) alone and in combination with L-PAM (dose range 0-0 microM) in a panel of 18 human neuroblastoma cell lines. BSO alone was highly cytotoxic with 16/18 neuroblastoma cell lines having IC90 values (range 2.1- > 1000 microM) below the clinically achievable steady-state plasma level of 500 microM BSO. Maximal cell killing correlated with GSH levels decreased to less than 10% baseline, and was partially reversed by the addition of exogenous anti-oxidants (GSH, vitamin E and ascorbate). Fluorocytometric analysis of DNA fragments by the Tunnel method detected 92% of a BSO sensitive cell line in apoptosis after a 48 h exposure to 500 microM BSO. The combination of L-PAM and BSO synergistically enhanced the cell killing of L-PAM alone by > 1-3 logs (combination index < 1). We conclude that BSO has significant single-agent cytotoxicity against neuroblastoma and enhances cell killing when combined with L-PAM.
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PMID:Buthionine sulphoximine alone and in combination with melphalan (L-PAM) is highly cytotoxic for human neuroblastoma cell lines. 951 45

CuZn superoxide dismutase (SOD) secretion was detected in media of [35S]cysteine-labeled human neuroblastoma SK-N-BE cells precipitated with antihuman CuZn SOD antibodies. The ability of Fe2+/ascorbate oxidative stress to induce CuZn SOD in SK-N-BE cells was evaluated by Western blot analysis. The results showed that, like human hepatocarcinoma cells and human fibroblasts, SK-N-BE cells secrete CuZn SOD. In addition, the CuZn SOD concentration was higher in cells subjected to oxidative stress than in unstressed cells. The secretion of CuZn SOD and the ability of Fe2+/ascorbate to increase its protein content in SK-N-BE cells indicates that this enzyme protects the brain from damage induced by oxidative stress.
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PMID:Secretion and increase of intracellular CuZn superoxide dismutase content in human neuroblastoma SK-N-BE cells subjected to oxidative stress. 957 Jul 22

The present study investigated the ability of two neuroblastoma cell lines (SK-N-SH, with one copy of N-myc, and SK-N-BE(2), with over 150 copies of N-myc) to recycle ascorbate by quantifying semidehydroascorbate reductase and dehydroascorbate reductase activities. Both cell lines expressed dehydroascorbate activity (SK-N-SH 28.4 +/- 9.8, SK-N-BE(2) 21.7 +/- 5.2 nmol/min/mg protein). Intracellular semidehydroascorbate activity was present only in SK-N-BE(2) cells (4.7 +/- 1.2 nmol/min/mg protein). Extracellular ascorbate was regenerated by semidehydroascorbate membrane activity, the activity of SK-N-BE(2) being twice that of SK-N-SH cells. The present data may explain the ability of the tumor to progress or regress through mechanisms involving both myc oncogene and apoptosis.
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PMID:Ascorbic acid recycling in N-myc amplified human neuroblastoma cells. 961 25

The process of iron (Fe) release from cells plays an important role in health and disease, although the mechanisms responsible remain unclear. In this study we have examined the process of Fe efflux from HepG2 cells, including the possible roles of Cp and ascorbate in this process. Recently, it has been suggested that Cp plays no role in Fe release but can increase Fe uptake by Fe-deficient HepG2 cells (Mukhopadhyay et al. Science 1998;279:714-7). However, this latter study used a nonphysiologically relevant Fe complex (iron 59-NTA) to label cells with 59Fe at a nonphysiologic temperature (25 degrees C) and Cp concentration (<100 microg/mL). Because of these problems, the experiments have been repeated by maintaining physiologic conditions and labeling cells with the physiologic Fe donor diferric Tf. When cells were labeled at 37 degrees C with 59Fe-Tf in the presence of a physiologically relevant Cp concentration (300 microg/mL), this latter protein had no effect on the uptake of 59Fe in control cells or in cells depleted of Fe by using desferrioxamine. In addition, when Fe-replete or Fe-depleted cells were incubated with 59Fe-NTA at 25 degrees C or 37 degrees C, Cp had no effect on 59Fe uptake compared with the control. When the effect of Cp (10-500 microg/mL) on 59Fe release was examined in cells prelabeled with 59Fe-Tf, a concentration-dependent increase in 59Fe efflux was observed, whereas BSA had no effect. However, in contrast to membrane-permeable Fe chelators that caused a marked increase in Fe release, the effect of Cp on Fe efflux was less impressive. To further investigate the mechanism of 59Fe mobilization, we compared 59Fe efflux among HepG2 cells, SK-Mel-28 melanoma cells, and SK-N-MC neuroblastoma cells. These studies demonstrated that 59Fe release was dependent on the incubation time with 59Fe-Tf, the cell line, and the reincubation temperature. Although 59Fe mobilization from cells was markedly temperature dependent, a range of metabolic inhibitors did not affect 59Fe release. Additional experiments showed that physiologic concentrations of ascorbate reduced 59Fe efflux, whereas glutathione had no effect. This study provides further evidence that Cp is involved in Fe mobilization but does not appear to affect Fe uptake from Tf or NTA.
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PMID:Role of ceruloplasmin and ascorbate in cellular iron release. 1056 Sep 33

Dopamine (DA), while an essential neurotransmitter, is also a known neurotoxin that potentially plays an etiologic role in several neurodegenerative diseases. DA metabolism and oxidation readily produce reactive oxygen species (ROS) and DA can also be oxidized to a reactive quinone via spontaneous, enzyme-catalyzed or metal-enhanced reactions. A number of these reactions are cytotoxic, yet the precise mechanisms by which DA leads to cell death remain unknown. In this study, the neuroblastoma cell line, SK-N-SH, was utilized to examine DA toxicity under varying oxidant states. Cells pretreated with the glutathione (GSH)-depleting compound, L-buthionine sulfoximine (L-BSO), exhibited enhanced sensitivity to DA compared to controls (non-GSH-depleted cells). Furthermore, in cells pretreated with L-BSO, the addition of ascorbate (250 microM) afforded significant protection against DA-induced toxicity, while pyruvate (500 microM) had no protective effect. To further characterize the possibility that DA is associated with oxidative stress, additional studies were carried out with manganese (30 microM) as a pro-oxidant. Manganese and DA (200 microM), although not cytotoxic when individually administered to SK-N-SH cells, had a synergistic action on cytotoxicity. Finally, morphological and molecular markers of programmed cell death (apoptosis) were observed in cells treated with DA and L-BSO. These markers included membrane blebbing and internucleosomal DNA fragmentation. These results suggest that DA toxicity is tightly linked to intracellular oxidant/antioxidant levels, and that environmental factors, such as excessive Mn exposure, may modulate cellular sensitivity to DA.
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PMID:Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by L-BSO and apoptosis. 1070 May 89

The dopamine analogue 6-hydroxydopamine (6-OHDA) is selectively toxic to catecholaminergic neurons. Because of its selectivity for neuroblastic cells in the sympathetic nervous system lineage, 6-OHDA has been suggested as a chemotherapeutic agent for targeted treatment of patients with neuroblastoma. We tested the hypothesis that the toxicity of 6-OHDA is caused by its interaction with serum ferric transferrin (Fe-TF) resulting in release of iron. We further hypothesized that this iron, through its redox-cycling by 6-OHDA, triggers generation of reactive oxygen species. 6-OHDA-induced release of iron from Fe-TF was demonstrated by: (1) low-temperature EPR spectroscopic evidence for decay of the characteristic Fe-TF signal (g = 4.3) and appearance of the high-spin signal from iron chelated by 6-OHDA oxidation products; (2) spectrophotometric detection of complexing of iron with the Fe(2+) chelator ferrozine; (3) redox-cycling of ascorbate yielding EPR-detectable ascorbate radicals; and (4) generation of hydroxyl radicals as evidenced by EPR spectroscopy of their adduct with a spin trap, 5, 5'-dimethylpyrroline oxide (DMPO) (DMPO-OH). Our low-temperature EPR studies showed that in human plasma, 6-OHDA caused iron release only under nitrogen gas but not under air or oxygen. The absence of a 6-OHDA effect in plasma under aerobic conditions was most likely due to its ferroxidase activity [with consequent reuptake of Fe(III) by apoTF] and catalytic oxidation of 6-OHDA by ceruloplasmin. Modeling of these plasma activities by a stable nitroxide radical, 2,2,6, 6-tetramethyl-1-piperidinyloxy (TEMPOL), resulted in protection of plasma Fe-TF against iron release under nitrogen. Parenteral administration of 6-OHDA to mice resulted in iron release from Fe-TF as evidenced by transformation of the Fe-TF low-temperature EPR signal that was indistinguishable from that seen in in vitro models. In addition, administration of the iron chelator deferoxamine (DFO) to mice prior to administration of toxic doses of 6-OHDA resulted in a decrease in activity impairment of mice as compared to that seen with 6-OHDA alone. These findings underscore the physiological and pharmacological relevance of 6-OHDA-mediated iron release from Fe-TF and suggest that iron chelators (DFO) may be used for prevention of 6-OHDA toxicity.
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PMID:Interaction between 6-hydroxydopamine and transferrin: "Let my iron go". 1072 33

Dopamine-beta-hydroxylase (DbetaH) is a copper-containing enzyme that uses molecular oxygen and ascorbate to catalyze the addition of a hydroxyl group on the beta-carbon of dopamine to form norepinephrine. While norepinephrine causes vasoconstriction following reflex sympathetic stimulation, nitric oxide (NO) formation results in vasodilatation via a guanylyl cyclase-dependent mechanism. In this report, we investigated the relationship between NO and DbetaH enzymatic activity. In the initial in vitro experiments, the activity of purified DbetaH was inhibited by the NO donor, diethylamine/NO (DEA/NO), with an IC(50) of 1 mm. The inclusion of either azide or GSH partially restored DbetaH activity, suggesting the involvement of the reactive nitrogen oxide species, N(2)O(3). Treatment of human neuroblastoma cells (SK-N-MC) with diethylamine/NO decreased cellular DbetaH activity without affecting their growth rate and was augmented by the depletion of intracellular GSH. Co-culture of the SK-N-MC cells with interferon-gamma and lipopolysaccharide-activated macrophages, which release NO, also reduced the DbetaH activity in the neuroblastoma cells. Our results are consistent with the hypothesis that nitrosative stress, mediated by N(2)O(3), can result in the inhibition of norepinephrine biosynthesis and may contribute to the regulation of neurotransmission and vasodilatation.
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PMID:Inhibitory effects of nitric oxide and nitrosative stress on dopamine-beta-hydroxylase. 1088 4

Calcineurin (CN) is a protein phosphatase involved in a wide range of cellular responses to calcium-mobilizing signals, and a role for this enzyme in neuropathology has been postulated. We have investigated the possibility that redox modulation of CN activity is relevant to neuropathological conditions where an imbalance in reactive oxygen species has been described. We have monitored CN activity in cultured human neuroblastoma SH-SY5Y cells and obtained evidence that CN activity is promoted by treatment with ascorbate or dithiothreitol and impaired by oxidative stress. Evidence for the existence of a redox regulation of this enzyme has been also obtained by overexpression of wild-type antioxidant Cu,Zn superoxide dismutase (SOD1) that promotes CN activity and protects it from oxidative inactivation. On the contrary, overexpression of mutant SOD1s associated with familial amyotrophic lateral sclerosis (FALS) impairs CN activity both in transfected human neuroblastoma cell lines and in the motor cortex of brain from FALS-transgenic mice. These data suggest that CN might be a target in the pathogenesis of SOD1-linked FALS.
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PMID:Calcineurin activity is regulated both by redox compounds and by mutant familial amyotrophic lateral sclerosis-superoxide dismutase. 1089 35


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