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 current work tested the hypothesis that the zinc status of a cell influences its sensitivity to iron-induced oxidative stress. Human IMR-32 neuroblastoma cells were cultured for 24 h in nonchelated control media (5 microM zinc; 4.5 microM iron), or in media that was treated with DTPA to reduce its zinc content (chelated media). Chelated media was supplemented with zinc to achieve concentrations of 1.5-50 microM Zn. The media was then replaced with serum-free complex media (0.9 microM Zn) with either no added iron (0.6 microM Fe), or iron (FeCl(3)) added at concentrations ranging from 15 to 100 microM. Cells were cultured for an additional 3- to 24-hour period. Over the 24-hour period, cells cultured in the control iron media had good viability, and they displayed the gross morphology typical of these cells in culture. With 100 microM iron, cell viability was low in all groups. After 24 h and at iron concentrations between 15-50 microM, cells that had been cultured in the low zinc-chelated media (1.5 microM Zn) showed a concentration-dependent increase in 5 (or 6)-carboxy-2'7'-dichlorodihydrofluorescein diacetate (DCDCDHF) fluorescence (oxidative stress) and decrease in cell viability. A positive correlation between both parameters was observed (r = 0.92). These cells had altered morphology and high level of nucleosomes suggestive of cell death by apoptosis. These results support the concept that the zinc status of IMR-32 neuroblastoma cells modulates their sensitivity to iron overload.
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PMID:Zinc status of human IMR-32 neuroblastoma cells influences their susceptibility to iron-induced oxidative stress. 1240 50

Heme, a major functional form of iron in the cell, is synthesized in the mitochondria by ferrochelatase inserting ferrous iron into protoporphyrin IX. Heme deficiency was induced with N-methylprotoporphyrin IX, a selective inhibitor of ferrochelatase, in two human brain cell lines, SHSY5Y (neuroblastoma) and U373 (astrocytoma), as well as in rat primary hippocampal neurons. Heme deficiency in brain cells decreases mitochondrial complex IV, activates nitric oxide synthase, alters amyloid precursor protein, and corrupts iron and zinc homeostasis. The metabolic consequences resulting from heme deficiency seem similar to dysfunctional neurons in patients with Alzheimer's disease. Heme-deficient SHSY5Y or U373 cells die when induced to differentiate or to proliferate, respectively. The role of heme in these observations could result from its interaction with heme regulatory motifs in specific proteins or secondary to the compromised mitochondria. Common causes of heme deficiency include aging, deficiency of iron and vitamin B6, and exposure to toxic metals such as aluminum. Iron and B6 deficiencies are especially important because they are widespread, but they are also preventable with supplementation. Thus, heme deficiency or dysregulation may be an important and preventable component of the neurodegenerative process.
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PMID:Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. 1241 55

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin used in cellular models of Parkinson's Disease. Although intracellular iron plays a crucial role in MPP(+)-induced apoptosis, the molecular signalling mechanisms linking iron, reactive oxygen species (ROS) and apoptosis are still unknown. We investigated these aspects using cerebellar granule neurons (CGNs) and human SH-SY5Y neuroblastoma cells. MPP(+) enhanced caspase 3 activity after 24 h with significant increases as early as 12 h after treatment of cells. Pre-treatment of CGNs and neuroblastoma cells with the metalloporphyrin antioxidant enzyme mimic, Fe(III)tetrakis(4-benzoic acid)porphyrin (FeTBAP), completely prevented the MPP(+)-induced caspase 3 activity as did overexpression of glutathione peroxidase (GPx1) and pre-treatment with a lipophilic, cell-permeable iron chelator [N, N '-bis-(2-hydroxybenzyl)ethylenediamine-N, N '-diacetic acid, HBED]. MPP(+) treatment increased the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labelling)-positive cells which was completely blocked by pre-treatment with FeTBAP. MPP(+) treatment significantly decreased the aconitase and mitochondrial complex I activities; pre-treatment with FeTBAP, HBED and GPx1 overexpression reversed this effect. MPP(+) treatment increased the intracellular oxidative stress by 2-3-fold, as determined by oxidation of dichlorodihydrofluorescein and dihydroethidium (hydroethidine). These effects were reversed by pre-treatment of cells with FeTBAP and HBED and by GPx1 overexpression. MPP(+)-treatment enhanced the cell-surface transferrin receptor (TfR) expression, suggesting a role for TfR-induced iron uptake in MPP(+) toxicity. Treatment of cells with anti-TfR antibody (IgA class) inhibited MPP(+)-induced caspase activation. Inhibition of nitric oxide synthase activity did not affect caspase 3 activity, apoptotic cell death or ROS generation by MPP(+). Overall, these results suggest that MPP(+)-induced cell death in CGNs and neuroblastoma cells proceeds via apoptosis and involves mitochondrial release of ROS and TfR-dependent iron.
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PMID:1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. 1252 38

The chelator currently used to treat iron (Fe) overload disease, desferrioxamine (DFO), has shown anti-proliferative activity against leukemia and neuroblastoma cells in vitro, in vivo and in clinical trials. Collectively, these studies suggest that Fe-deprivation may be a useful anti-cancer strategy. However, the efficacy of DFO is severely limited due to its poor ability to permeate cell membranes and bind intracellular Fe pools. These limitations have encouraged the development of other Fe chelators that are far more effective than DFO. One group of ligands that have been extensively investigated are those of the pyridoxal isonicotinoyl hydrazone (PIH) class. In this review the marked anti-proliferative effects of the PIH analogs are discussed with reference to their mechanisms of action and structure-activity relationships. In particular, we discuss the activity of a novel group of ligands that are "hybrid" chelators derived from our most effective PIH analogs and thiosemicarbazones. The anti-tumor activity of the PIH analogs and other chelators such as tachpyridine, O-trensox and the desferrithiocin analogs have been well characterized in vitro. However, further studies in animals are critical to evaluate their selective anti-tumor activity and potential as therapeutic agents.
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PMID:Iron chelators as anti-neoplastic agents: current developments and promise of the PIH class of chelators. 1267 75

The exact pathogenesis of neuronal death following bleeding in brain parenchyma is still unknown. Hemoglobin (Hb) toxicity has been postulated to be one of the underlying mechanisms. The purpose of this study was to examine the possible contribution to neurotoxicity of each of the Hb compounds and to characterize the death pathway. Pheochromocytoma (PC12) and neuroblastoma (SH- SY5Y) cell lines were exposed to Hb, globin, hemin, protoporphyrin IX and iron for 1.5- 24 h. We found that Hb and hemin are highly toxic (LD(50) of 8 and 20 &mgr; mol/l, respectively) as compared to globin that was not toxic. In addition, protoporphyrin IX and iron, compounds of hemin, were less toxic than hemin itself (LD(50) of 962 and 2070 &mgr; mol/l respectively). We also demonstrated that non-specific protein digestion with proteinase-K, markedly increased Hb toxicity. Hemin-treated cells caused a typical apoptotic cell death pattern as indicated by DNA fragmentation, caspase activation and reduction in the mitochondrial membrane potential. Treatment with the antioxidant N-acetyl-L-cysteine or iron chelator, deferoxamine, diminished hemin-induced cell death, indicating a role of oxidative stress in this deleterious process. Thus, therapeutic strategies, based on antioxidant, iron chelator and anti-apoptotic agents may be effective in counteracting Hb neurotoxicity.
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PMID:Hemin-induced apoptosis in PC12 and neuroblastoma cells: implications for local neuronal death associated with intracerebral hemorrhage. 1270 99

Ceruloplasmin (CP) is a copper-dependent ferroxidase. It regulates iron metabolism and is involved in inflammation, angiogenesis, and protection against oxidative stress. CP also modulates K(+) channel activity in neuroblastoma cells and affects cardiodynamics of isolated hearts. Considering the presence of CP in the nervous system and the importance of iron ions and K(+) channels in neuronal activity, we postulated a role of CP in neuronal development. This hypothesis was tested using the P19 mouse embryonal carcinoma cell line, a model of neuronal differentiation. Addition of CP to the culture medium of newly differentiated P19 neurons induced cell aggregation within 24 h. This effect was concentration-dependent half-maximal at 50 nM, and not associated with necrosis, apoptosis or changes in secretory function. Deglycosylated CP was aggregative but not denatured CP, copper salts, His(2)Cu complex, or other copper enzymes or serum proteins. CP-induced aggregation was less pronounced with aging neurons and seemed not to involve K(+) channels. Immunocytofluorescence analysis demonstrated that digoxigenin-labeled CP bound to P19 neurons and the proportion of responding neurons decreased with aging. The interaction of digoxigenin-labeled CP with neurons was half-maximal at 120 nM by enzyme-linked immunosorbent assay and displaced by unlabeled CP. Our data indicate a specific aggregative action of CP on young neurons in vitro, possibly involving CP receptors. A potential developmental role of CP in nervous system organization is thus demonstrated.
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PMID:The blue copper ceruloplasmin induces aggregation of newly differentiated neurons: a potential modulator of nervous system organization. 1294 1

We screened for drugs that specifically interact with the 5'-untranslated region of the mRNA encoding the Alzheimer's amyloid precursor protein (APP). Our goal was to use newly discovered APP 5' UTR directed compounds to limit amyloid-beta (Abeta)-peptide output in cell culture systems. The APP 5' UTR folds into a stable RNA secondary structure (Gibbs free energy: DeltaG = -54.9 kcal/mol) and is an important regulator of the amount of APP translated in response to IL-1 (Nilsson et al., 1998; Rogers et al., 1999) and iron (Rogers et al., 2002). Seventeen drug "hits" were identified from a library of 1,200 FDA preapproved drugs (Rogers et al., 2002). Six of the original 17 compounds were validated for their capacity to suppress reporter gene expression in stable neuroblastoma transfectants expressing the dicistronic reporter construct shown in Fig. 2. These six leads suppressed APP 5' UTR driven luciferase translation while causing no effect on the translation of dicistronic GFP gene translated from a viral IRES (negative control to ensure specificity during drug screens). In this report, we show that paroxetine (serotonin reuptake blocker) and dimercaptopropanol (Hg chelator) exerted significant effects on APP expression (steady-state levels of APP), whereas Azithromycin altered APP processing. None of these three compounds altered APLP-1 expression. In the future, we will identify further novel compounds that influence Abeta levels, either via translation inhibition or by changing the activity of proteins coupled between APP translation and APP processing.
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PMID:Drug discovery targeted to the Alzheimer's APP mRNA 5'-untranslated region: the action of paroxetine and dimercaptopropanol. 1450 Oct 7

The established or potentially toxic agents implicated in the nigral cell death in Parkinson's disease, dopamine, 1-methyl-4-phenylpyridinium (MPP(+)), iron, and manganese, were examined as to their effects on the viability of cells overexpressing alpha-synuclein. SK-N-MC neuroblastoma cells stably expressing the human dopamine transporter were transfected with human alpha-synuclein and cell clones with and without alpha-synuclein immunoreactivity were obtained. Cells were exposed for 24-72 h to 1-10 microM dopamine, 0.1-3 microM MPP(+), 0.1-1 mM FeCl(2) or 30-300 microM MnCl(2) added to the culture medium. There was no difference between cells expressing alpha-synuclein and control cells after exposure to dopamine, MPP(+) or FeCl(2). However, MnCl(2) resulted in a significantly stronger decreased viability of cells overexpressing alpha-synuclein after 72 h. These findings suggest that manganese may co-operate with alpha-synuclein in triggering neuronal cell death such as seen in manganese parkinsonism. The relevance of our observations for the pathoetiology of Parkinson's disease proper remains to be determined.
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PMID:alpha-Synuclein selectively increases manganese-induced viability loss in SK-N-MC neuroblastoma cells expressing the human dopamine transporter. 1469 76

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin that causes Parkinson's disease in experimental animals and humans. Despite the fact that intracellular iron was shown to be crucial for MPP(+)-induced apoptotic cell death, the molecular mechanisms for the iron requirement remain unclear. We investigated the role of transferrin receptor (TfR) and iron in modulating the expression of alpha-synuclein (alpha-syn) in MPP(+)-induced oxidative stress and apoptosis. Results show that MPP(+) inhibits mitochondrial complex-1 and aconitase activities leading to enhanced H(2)O(2) generation, TfR expression and alpha-syn expression/aggregation. Pretreatment with cell-permeable iron chelators, TfR antibody (that inhibits TfR-mediated iron uptake), or transfection with glutathione peroxidase (GPx1) enzyme inhibits intracellular oxidant generation, alpha-syn expression/aggregation, and apoptotic signaling as measured by caspase-3 activation. Cells overexpressing alpha-syn exacerbated MPP(+) toxicity, whereas antisense alpha-syn treatment totally abrogated MPP(+)-induced apoptosis in neuroblastoma cells without affecting oxidant generation. The increased cytotoxic effects of alpha-syn in MPP(+)-treated cells were attributed to inhibition of mitogen-activated protein kinase and proteasomal function. We conclude that MPP(+)-induced iron signaling is responsible for intracellular oxidant generation, alpha-syn expression, proteasomal dysfunction, and apoptosis. Relevance to Parkinson's disease is discussed.
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PMID:Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. 1474 48

The neurotoxin, 6-hydroxydopamine (6-OHDA) has been implicated in the neurodegenerative process of Parkinson's disease. The current study was designed to elucidate the toxicological effects of 6-OHDA on energy metabolism in neuroblastoma (N-2A) cells. The toxicity of 6-OHDA corresponds to the total collapse of anaerobic/aerobic cell function, unlike other mitochondrial toxins such as MPP+ that target specific loss of aerobic metabolism. The toxicity of 6-OHDA paralleled the loss of mitochondrial oxygen (O2) consumption (MOC), glycolytic activity, ATP, H+ ion gradients, membrane potential and accumulation of the autoxidative product, hydrogen peroxide (H2O2). Removing H2O2 with nonenzymatic stoichiometric scavengers, such as carboxylic acids, glutathione and catalase yielded partial protection. The rapid removal of H2O2 with pyruvate or catalase restored only anaerobic glycolysis, but did not reverse the loss of MOC, indicating mitochondrial impairment is independent of H2O2. The H2O2 generated by 6-OHDA contributed toward the loss of anaerobic glycolysis through lipid peroxidation and lactic acid dehydrogenase inhibition. The ability of 6-OHDA to maintain oxidized cytochrome c (CYT-C-OX) in its reduced form (CYT-C-RED), appears to play a role in mitohondrial impairment. The reduction of CYT-C by 6-OHDA, was extensive, occurred within minutes, preceded formation of H2O2 and was unaffected by catalase or superoxide dismutase. At similar concentrations, 6-OHDA readily altered the valence state of iron [Fe(III)] to Fe(II), which would also theoretically sustain CYT-C in its reduced form. In isolated mitochondria, 6-OHDA had negligible effects on complex I, inhibited complex II and interfered with complex III by maintaining the substrate, CYT-C in a reduced state. 6-OHDA caused a transient and potent surge in isolated cytochrome oxidase (complex IV) activity, with rapid recovery as a result of 6-OHDA recycling CYT-C-OX to CYT-C-RED. Typical mitochondrial toxins such as MPP+, azide and antimycin appeared to inhibit the catalytic activity of ETC enzymes. In contrast, 6-OHDA alters the redox of the cytochromes, resulting in loss of substrate availability and obstruction of oxidation-reduction events. Complete cytoprotection against 6-OHDA toxicity and restored MOC was achieved by combining catalase with CYT-C (horse heart). In summary, CYT-C reducing properties are unique to catecholamine neurotransmitters, and may play a significant role in selective vulnerability of dopaminergic neurons to mitochondrial insults.
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PMID:The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro. 1503 17

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