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)

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

Iron deficiency and iron chelators are known to alter folate metabolism in mammals, but the underlying biochemical mechanisms have not been established. Although many studies have demonstrated that the iron chelators mimosine and deferoxamine inhibit DNA replication in mammalian cells, their mechanism of action remains controversial. The effects of mimosine on folate metabolism were investigated in human MCF-7 cells and SH-SY5Y neuroblastoma. Our findings indicate that mimosine is a folate antagonist and that its effects are cell-specific. MCF-7 cells cultured in the presence of 350 microm mimosine were growth-arrested, whereas mimosine had no effect on SH-SY5Y cell proliferation. Mimosine altered the distribution of folate cofactor forms in MCF-7 cells, indicating that mimosine targets folate metabolism. However, mimosine does not influence folate metabolism in SH-SY5Y neuroblastoma. The effect of mimosine on folate metabolism is associated with decreased cytoplasmic serine hydroxymethyltransferase (cSHMT) expression in MCF-7 cells but not in SH-SY5Y cells. MCF-7 cells exposed to mimosine for 24 h have a 95% reduction in cSHMT protein, and cSHMT promoter activity is reduced over 95%. Transcription of the cSHMT gene is also inhibited by deferoxamine in MCF-7 cells, indicating that mimosine inhibits cSHMT transcription by chelating iron. Analyses of mimosine-resistant MCF-7 cell lines demonstrate that although the effect of mimosine on cell cycle is independent of its effects on cSHMT expression, it inhibits both processes through a common regulatory mechanism.
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PMID:Mimosine is a cell-specific antagonist of folate metabolism. 1076 49

CHP212 neuroblastoma cells were exposed to two different nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine and sodium nitroprusside. Apoptosis and necrosis were determined with flow cytometric analysis of annexin V binding and propodium iodide uptake. Both S-nitroso-N-acetylpenicillamine and sodium nitroprusside induced apoptosis, but with a different time dependency. Oxyhemoglobin (NO scavenger) attenuated the toxicity of S-nitroso-N-acetylpenicillamine, but had no effect on the toxicity of sodium nitroprusside. By contrast, deferoxamine (iron chelator) attenuated the toxicity of sodium nitroprusside, but had no effect on the toxicity of S-nitroso-N-acetylpenicillamine. Urate (ONOO(-) scavenger) did not influence the toxicity of either S-nitroso-N-acetylpenicillamine or sodium nitroprusside, but protected from SIN-1 (3-morpholinosydnonimine, ONOO(-) donor). It was shown that both dithiothreitol and ascorbic acid affected the toxicity of S-nitroso-N-acetylpenicillamine and sodium nitroprusside in opposite ways. In the presence of dithiothreitol, superoxide dismutase and catalase decreased the toxicity of sodium nitroprusside. In the presence of cells, but not in their absence, S-nitroso-N-acetylpenicillamine decomposed with a half-life of about 4 h as assessed by the production of nitrite and absorbance reduction at 335 nm. Sodium nitroprusside decomposed very slowly in the presence of cells as assessed by the production of ferrocyanide. It can be concluded that (1) slow and sustained release of NO from S-nitroso-N-acetylpenicillamine at the cell surface causes apoptosis in CHP212 cells, probably without the involvement of ONOO(-), (2) sodium nitroprusside causes apoptosis by the production of H(2)O(2) and/or iron, rather than NO, and probably has to be taken up by the cell for decomposition.
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PMID:S-nitroso-N-acetylpenicillamine and nitroprusside induce apoptosis in a neuronal cell line by the production of different reactive molecules. 1091 81

Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in alpha-synuclein can cause familial PD and that alpha-synuclein accumulates in Lewy bodies suggest that alpha-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P alpha-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain alpha-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of alpha-synuclein expressed and the type of alpha-synuclein expressed, with the amount of alpha-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, alpha-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing alpha-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that alpha-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD.
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PMID:The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. 1093 54

MPP(+), an active metabolite of MPTP, causes a dopaminergic neuronal degeneration similar to that observed in Parkinson's disease. Current data suggest that MPP(+)-induced cytotoxicity may be mediated by oxygen free radicals. To evaluate this hypothesis, we first investigated whether MPP(+) could cause oxidative stress by producing oxygen free radicals in the SH-SY5Y, human neuroblastoma cell line. MPP(+) was toxic to the cells dose-dependently but did not increase the level of lipid peroxidation at toxic concentrations. Second, we examined the effects of various antioxidants and an inhibitor of nitric oxide synthase (NOS) on the development of MPP(+) cytotoxicity. Pretreatment with antioxidants such as ascorbic acid, Trolox, phenyl-tertiary-butyl-nitrone (PBN), which show protective effects on tert-butyl hydroperoxide (tBOOH) toxicity did not attenuate MPP(+) cytotoxicity. Similarly, the combination of antioxidant enzymes, SOD and catalase (50 U/ml, respectively), did not protect the cells from the toxic action of MPP(+). Also N-nitro-l-arginine methyl ester (NAME), a competitive inhibitor of NOS, and combined incubation with NAME and antioxidant enzymes failed to attenuate MPP(+) cytotoxicity. On the other hand, a sublethal dose of MPP(+) potentiated iron and H(2)O(2)-induced cytotoxicity. These results suggest that oxygen free radicals may not be a primary cause of MPP(+)-induced cell death but that MPP(+) increases the vulnerability of cells to oxidative stress.
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PMID:MPP(+) increases the vulnerability to oxidative stress rather than directly mediating oxidative damage in human neuroblastoma cells. 1096 95

The activity of the superoxide-sensitive enzyme aconitase was monitored to evaluate the generation of superoxide in neuronal cell lines treated with beta-amyloid (Abeta) peptide 1-42. Treatment of differentiated and undifferentiated rat PC12 and human neuroblastoma SK-N-SH cells with soluble Abeta1-42 (Abeta-derived diffusible ligands) or fibrillar Abeta1-42 caused a 35% reversible inactivation of aconitase, which preceded loss of viability and was correlated with altered cellular function. Aconitase was reactivated upon incubation of cellular extracts with iron and sulfur, suggesting that Abeta causes the release of iron from 4Fe-4S clusters. Abeta neurotoxicity was partially blocked by the iron chelator deferoxamine. These data suggest that increased superoxide generation and the release of iron from 4Fe-4S clusters are early events in Abeta1-42 neurotoxicity.
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PMID:Reversible inactivation of superoxide-sensitive aconitase in Abeta1-42-treated neuronal cell lines. 1103 87

There have been many attempts to discover neuroprotective drugs for the treatment of Parkinson's disease (PD). Many of these compounds either do not cross the blood brain barrier or are not very effective in the 6-hydroxydopamine or MPTP (N-methyl-4-phenyl-1,2,3,6-terahydropyridine) models of PD. We have examined several compounds including dopamine receptor agonist bromocritine, lisuride, pergolide and R-apomorphine for their neuroprotective action against the above neurotoxins in PC12 and dopamine neuroblastoma cell lines in culture and in vivo. R-apomorphine exhibited relatively potent neuroprotective action in vitro, cell culture and in vivo as a radical scavenger and iron chelator, because of its catechol structure. The recent clinical trials with apomorphine, where parkinsonian subjects can be weaned off L-dopa would suggest that this drug either exerts a neuroprotective action or that continuous sustained stimulation of dopamine receptor may be responsible for its unusual pharmacological activity. Apomorphine has a far more broad neuroprotective activity in the various models as compared with 1-selegiline and may therefore be an ideal drug to study neuroprotection in parkinsonian subjects with the use of PET or SPECT.
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PMID:Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist; apomorphine. 1112 15

Neuroblastoma is the second most common solid malignancy of childhood. Enhanced expression of the amplified N-myc gene in the tumor cells may be associated with poor patient prognosis and may contribute to tumor development and progression. The use of deferoxamine mesylate (DFO), an iron chelator, to treat neuroblastoma is being investigated in national clinical studies. We show here by TUNEL assay and DNA laddering that DFO induces apoptosis in cultured human neuroblastoma cells, which is preceded by a decrease in the expression of N-myc and the altered expression of some other oncogenes (up-regulating c-fos and down-regulating c-myb) but not housekeeping genes. The decrease in N-myc expression is iron-specific but does not result from inhibition of ribonucleotide reductase, because specific inhibition of this iron-containing enzyme by hydroxyurea does not affect N-myc protein levels. Nuclear run-on and transient reporter gene expression experiments show that the decrease in N-myc expression occurs at the level of initiation of transcription and by inhibiting N-myc promoter activity. Comparison across neuroblastoma cell lines of the amount of residual cellular N-myc protein with the extent of apoptosis measured as pan-caspase activity after 48 h of iron chelation reveals no correlation, suggesting that the decrease in N-myc expression is unlikely to mediate apoptosis. In conclusion, chelation of cellular iron by DFO may alter the expression of multiple genes affecting the malignant phenotype by multiple pathways. Given the clinical importance of N-myc overexpression in neuroblastoma malignancy, decreasing N-myc expression by DFO might be useful as an adjunct to current
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PMID:Inhibition of N-myc expression and induction of apoptosis by iron chelation in human neuroblastoma cells. 1122 35

We have elucidated a biochemical mechanism whereby changes in iron metabolism cause changes in folate-dependent one-carbon metabolism. Although animal and clinical studies have demonstrated that perturbations in iron status and metabolism alter folate metabolism, the biochemical mechanisms underlying these associations have yet to be identified. The effect of altered ferritin expression on folate metabolism was determined in human MCF-7 cells and SH-SY5Y neuroblastoma. Cells expressing rat heavy chain ferritin (HCF) exhibited markedly increased expression of the folate-dependent enzyme cytoplasmic serine hydroxymethyltransferase (cSHMT). These effects were not seen when rat light chain ferritin was expressed. Additionally, cSHMT expression was not altered when HCF expression was induced in MCF-7 cells cultured with supplemental ferric citrate. This indicates that cSHMT expression is increased by elevated HCF concentrations, independent of increased iron availability, suggesting that cSHMT expression may respond to HCF-induced chelation of the regulatory iron pool. Increased HCF expression did not alter cSHMT mRNA levels, but did increase translation rates of cSHMT mRNA. The increase in translation was mediated, at least in part, through the cSHMT 5'-untranslated region of the transcript. MCF-7 cells with increased expression of cSHMT displayed increased efficiency of de novo thymidylate biosynthesis, indicating that thymidylate synthesis is normally limited by cSHMT activity in MCF-7 cells. Our data suggest that the iron regulatory pool may play an important role in regulating folate metabolism and thereby thymidine biosynthesis.
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PMID:Heavy chain ferritin enhances serine hydroxymethyltransferase expression and de novo thymidine biosynthesis. 1127 96

The reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the Abeta precursor protein (betaAPP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces betaAPP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in betaAPP processing. Phenserine treatment resulted in decreased secretion of soluble betaAPP and Abeta into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of betaAPP protein expression by phenserine was posttranscriptional as it suppressed betaAPP protein expression without altering betaAPP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5'-mRNA leader sequence of betaAPP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces Abeta levels by regulating betaAPP translation via the recently described iron regulatory element in the 5'-untranslated region of betaAPP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of betaAPP expression that can result in a substantial reduction in the level of Abeta.
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PMID:Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. 1140 70

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