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 effects of different calcium-mobilizing agents on cell death were characterized in NG108-15 neuroblastoma x glioma hybrid cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) increased the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and caused cell death. Thapsigargin (TG) not only increased the [Ca(2+)](i) and caused cell death but also induced neurite outgrowth via activation of phospholipase A(2) and cytochrome P450 epoxygenase. In contrast, bradykinin increased the [Ca(2+)](i), but had no effect on cell morphology or cell death. Cell death occurred by two different mechanisms, one of which was caspase-3-dependent and the other caspase-3-independent. Caspase-3 activation was Ca(2+)-dependent, whereas neurite outgrowth was Ca(2+)-independent. TG- or FCCP-induced caspase-3 activation occurred at the same time, but the cell death induced by TG was delayed. TG treatment did not enhance the generation of nitric oxide or cAMP or secretion of glial-derived neurotrophic factor or neurotrophin-3, but activated sphingosine kinase. Furthermore, inhibition of sphingosine kinase accelerated TG-induced cell death, and exogenous sphingosine 1-phosphate (S1P) protected cells from FCCP-induced cell death by about 60%. These results indicate that, in these cells, depletion of intracellular nonmitochondrial or mitochondrial Ca(2+) stores causes cell death, that TG activates phospholipase A(2) and sphingosine kinase, and that arachidonic acid induces neurite outgrowth, whereas S1P delays cell death.
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PMID:Distinct effects of different calcium-mobilizing agents on cell death in NG108-15 neuroblastoma X glioma cells. 1185 28

Freshly solubilized A beta peptides synergistically increase the magnitude of the constriction induced by endothelin-1 (ET-1), via the activation of a pro-inflammatory pathway. We report that mevinolin and mevastatin, two inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are able to completely abolish the vasoactive properties of A beta in rat aortae. Mevinolin also appears to oppose the increased vascular reactivity to ET-1 induced by interleukin 1-beta and phospholipase A(2) suggesting that statins display some anti-inflammatory properties. We show that freshly solubilized A beta stimulates prostaglandin E(2) and F(2 alpha) production (by 6 and 3.6 times, respectively) in isolated rat aortae and that mevinolin completely antagonizes this effect confirming the anti-inflammatory action of mevinolin ex vivo in rat aortae. In addition, we observed that A beta vasoactivity is not mediated nor modulated by mevalonic acid suggesting that the anti-inflammatory action of the statins are not related to an inhibition of HMG-CoA reductase activity. Differentiated human neuroblastoma cells (IMR32) were used to assess the neurotoxic effect of pre-aggregated A beta by quantifying the release of lactate dehydrogenase (LDH) in the cell culture medium. A beta appears to enhance LDH release by 30% in IMR32 cells, an effect that can be completely opposed by mevastatin. Taken together these data show that statins can antagonize the effect of A beta in different assays and provide new clues to understand the prophylactic action of the statins against Alzheimer's disease.
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PMID:Statins inhibit A beta-neurotoxicity in vitro and A beta-induced vasoconstriction and inflammation in rat aortae. 1188 11

The synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with chemotherapeutic drugs used to treat neuroblastoma. The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving cellular signaling pathways as yet incompletely defined but, in part, involving the generation of reactive oxygen species (ROS). In an attempt to characterize the mechanism of action of fenretinide, cDNA array filters were screened to identify apoptotic genes regulated in response to treatment of SH-SY5Y cells with fenretinide. Expression of the stress-induced transcription factor, GADD153, was up-regulated at both the protein and mRNA levels in response to fenretinide. Overexpression of GADD153 increased apoptosis in the presence and absence of fenretinide, whereas reduced expression of GADD153 by expression of antisense DNA abrogated the response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-beta/gamma agonist, RARbeta/gamma antagonists did not block the induction of GADD153 by fenretinide; conversely, the induction of GADD153 was blocked by antioxidants. Enzyme inhibitors were used to identify pathways mediating the ROS-dependent effects of fenretinide: inhibitors of phospholipase A(2) and lypoxygenases (LOX), and specific inhibitors of 12-LOX, but not 5-LOX or 15-LOX, inhibited the induction of ROS, apoptosis, and GADD153 in response to fenretinide. The inhibition of ROS and apoptosis was reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid (12-HpETE) and 12 (S)-hydroxyeicosatetraenoic acid (12-HETE). Fenretinide did not increase free arachidonic acid levels, but increased LOX activity without a detectable increase in 12-LOX protein. These results suggest that fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterized by a fenretinide-dependent increase in 12-LOX activity, leading to the induction of GADD153. The targeting of 12-LOX and/or GADD153 in neuroblastoma cells may thus present a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.
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PMID:GADD153 and 12-lipoxygenase mediate fenretinide-induced apoptosis of neuroblastoma. 1223 79

Compound 24, an alkyl-substituted amino acid amide, previously found to activate pertussis toxin-sensitive G proteins in cell membranes and membrane protein fractions, was used as a tool to determine the mechanism/location of nicotine inhibition of amyloid beta peptide-stimulated phospholipase A2 and D activities in a human neuroblastoma cell line, LA-N-2, in vitro. In contrast to our previous findings with amyloid beta peptide, these phospholipase activations by compound 24 were not inhibited by (-)-nicotine, cholera toxin or tetanus toxin pretreatment. The contrasting activation of these phospholipases by amyloid beta peptide and compound 24 are discussed.
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PMID:Activation of phospholipases A2 and D of a human neuroblastoma cell line (LA-N-2) by N-dodecyl-L-lysine amide (compound 24), a putative G protein activator: characteristics of inhibition by (-)-nicotine. 1251 13

The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving signaling pathways mediated by free radicals or reactive oxygen species (ROS). The aim of this study was to identify mechanisms generating ROS and apoptosis of neuroblastoma cells in response to fenretinide. Fenretinide-induced ROS or apoptosis of SH-SY5Y or HTLA 230 neuroblastoma cells were not blocked by Nitro l-argenine methyl ester (l-NAME), an inhibitor of nitric oxide synthase. Flavoprotein-dependent superoxide-producing enzymes such as NADPH oxidase were also not involved in fenretinide-induced apoptosis or ROS generation. Similarly, ketoconazole, a cytochrome P450 inhibitor, and inhibitors of cyclooxygenase (COX) were also ineffective. In contrast, inhibition of phospholipase A(2) or lipoxygenases (LOX) blocked the induction of ROS and apoptosis in response to fenretinide. Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis. The effects of eicosatriynoic acid, a specific 12-LOX inhibitor, were reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid and 12 (S)-hydroxyeicosatetraenoic acid. The targeting of 12-LOX in neuroblastoma cells may thus be a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.
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PMID:Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma. 1285 36

The aim of this study was to investigate the mechanism of the cytotoxic effect of beta-bungarotoxin (beta-BuTX), a presynaptic neurotoxin, on rat cerebellar granule neurons (CGNs). The maturation of CGNs is characterized by the prominent dense neurite networks that became fragmented after treatment with beta-BuTX, and this cytotoxic effect of beta-BuTX on CGNs was in a dose- and time-dependant manner. The cytotoxic effect of beta-BuTX was found to be more potent than other toxins, such as alpha-BuTX, cardiotoxin, melittin, and Naja naja atra venom phospholipase A(2). Meanwhile, undifferentiated neuroblastoma neuronal cell lines, IMR-32 and SK-N-MC, and astrocytes were found to be resistant to beta-BuTX. These results indicated that only the mature CGNs were sensitive to beta-BuTX insults. None of the following chemicals: antioxidants, K(+)-channel activator, K(+)-channel antagonists, intracellular Ca(2+) chelator, Ca(2+)-channel blockers, NMDA receptor antagonists, and nitric oxide synthase inhibitor tested, were able to reduce beta-BuTX-induced cytotoxicity. However, secretory type phospholipase A(2) inhibitors (glycyrrhizin and aristolochic acid) and a free radical scavenger (5,5-dimethyl pyrroline N-oxide, DMPO) could attenuate not only beta-BuTX-induced cytotoxicity but also ROS production and caspase-3 activation. These data suggest that phospholipase A(2) activity of beta-BuTX may be responsible for free radical generation and caspase-3 activation that accounts for the observed cytotoxic effect. It is proposed that the CGNs can be a useful tool for studying interactions of the molecules on neuronal plasma membrane with beta-BuTX that mediates the specific cytotoxicity.
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PMID:Phospholipase A(2) activity of beta-bungarotoxin is essential for induction of cytotoxicity on cerebellar granule neurons. 1584 37

Modification of His-47 and removal of the N-terminal octapeptide caused a different effect on the structure of Naja naja atra (Taiwan cobra) phospholipase A2 (PLA2). Unlike native enzyme, Ca2+ induced an alteration in the structural flexibility of His-modified PLA2. Moreover, the spatial positions of Trp residues in His-modified PLA2 were not properly rearranged toward lipid-water interface in the presence of Ca2+. CD spectra and fluorescence measurement showed that the dynamic properties of Trp residues and the gross conformation of N-terminally truncated PLA2 were totally different from native enzyme. Although a precipitous drop in the enzymatic activity was observed with modified PLA2, His-modified PLA2 and N-terminally truncated PLA2 retained cytotoxicity on inducing necrotic death of human neuroblastoma SK-N-SH cells. Our data suggest that structural perturbations elicited by the chemical modification cause a dissociation of enzymatic activity and cytotoxicity of PLA2.
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PMID:The structural and functional contribution of N-terminal region and His-47 on Taiwan cobra phospholipase A2. 1800 83

Modification of catalytic residue His-47 with p-bromophenacyl bromide (BPB) abolished the enzymatic activity of Naja naja atra phospholipase A2 (PLA2). Additionally, alterations in the global structure and the spatial positions of Trp residues were noted in His-modified PLA2. The cell viability of human neuroblastoma SK-N-SH cells was decreased by approximately 40% and 20% after treatment with 10 microM PLA2 and BPB-PLA2, respectively. Native and His-modified PLA2 induced a necrotic cell death accompanied with an activation of p38 MAPK, the loss of mitochondrial membrane potential (DeltaPsim) and cytochrome c release. Pretreatment with SB202190 (p38 MAPK inhibitor) and cyclosporine A (inhibitor of mitochondria permeability transition pore) rescued cell viability, DeltaPsim and cytochrome c release of PLA2-treated cells. Taken together, our data indicate that PLA2 activity does not play an indispensable role on the cytotoxicity of N. naja atra PLA2, and suggest a novel function of secretory PLA2 in inducing cell death of neuroblastoma. Moreover, the reduced cytotoxicity noted with BPB-PLA2 may be partly attributed to conformational distortion after modification of His-47.
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PMID:p38 MAPK activation and mitochondrial depolarization mediate the cytotoxicity of Taiwan cobra phospholipase A2 on human neuroblastoma SK-N-SH cells. 1858 42

The aim of the present study is to elucidate the signaling pathway involved in death of human neuroblastoma SK-N-SH cells induced by Naja naja atra phospholipase A(2) (PLA(2)). Upon exposure to PLA(2), p38 MAPK activation, ERK inactivation, ROS generation, increase in intracellular Ca(2+) concentration, and upregulation of Fas and FasL were found in SK-N-SH cells. SB202190 (p38MAPK inhibitor) suppressed upregulation of Fas and FasL. N-Acetylcysteine (ROS scavenger) and BAPTA-AM (Ca(2+) chelator) abrogated p38 MAPK activation and upregulation of Fas and FasL expression, but restored phosphorylation of ERK. Activated ERK was found to attenuate p38 MAPK-mediated upregulation of Fas and FasL. Deprivation of catalytic activity could not diminish PLA(2)-induced cell death and Fas/FasL upregulation. Moreover, the cytotoxicity of arachidonic acid and lysophosphatidylcholine was not related to the expression of Fas and FasL. Taken together, our results indicate that PLA(2)-induced cell death is, in part, elicited by upregulation of Fas and FasL, which is regulated by Ca(2+)- and ROS-evoked p38 MAPK activation, and suggest that non-catalytic PLA(2) plays a role for the signaling pathway.
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PMID:Upregulation of Fas and FasL in Taiwan cobra phospholipase A2-treated human neuroblastoma SK-N-SH cells through ROS- and Ca2+-mediated p38 MAPK activation. 1900 58

Taiwan cobra phospholipase A(2) (PLA(2)) treatment promoted proADAM17 processing into mature ADAM17 in human neuroblastoma SK-N-SH cells. The abolishment of catalytic activity caused a drastic drop in the PLA(2) ability to induce ADAM17 maturation, and lysophosphatidylcholine treatment mimicked the effect of PLA(2). ADAM17 activity measurement, ADAM17 cell surface levels, TNFR2 ectodomain shedding, and ADAM17 mRNA transcription supported that posttranscriptional up-regulation of ADAM17 occurred in PLA(2)-treated SK-N-SH cells. PLA(2) treatment induced p38 MAPK activation and ERK inactivation. p38 MAPK activation suppression by SB202190 (p38 MAPK inhibitor) abolished posttranscriptional up-regulation of ADAM17 in PLA(2)-treated cells, while treatment with U0126 (MEK1 and MEK2 inhibitor) increased ADAM17 maturation in SK-N-SH cells. Constitutively active MEK1 expression abrogated PLA(2)-induced ADAM17 maturation. Taken together, our data indicate that PLA(2)-evoked p38 MAPK activation and ERK inactivation are involved in ADAM17 posttranscriptional up-regulation, and suggest that the action of PLA(2) is catalytic activity-dependent.
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PMID:Taiwan cobra phospholipase A2 elicits posttranscriptional up-regulation of ADAM17 in human neuroblastoma SK-N-SH cells. 2050 6


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