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)

Glial cells interact with neurons and play important roles in the development, differentiation, maintenance and repair of the nervous system. Human neuroblastoma cells (SH-SY5Y) became dramatically resistant to neurotoxin 6-hydroxydopamine (6-OHDA), when co-cultured with mouse astrocytes. In order to further delineate the molecular mechanism involved in the neuroprotection in this selective cell-cell interaction, we assessed the activation of two signal pathways, namely, the MAP kinases (extracellular signal-regulated kinases, ERK1/2) and phosphoinositide 3-kinase (PI3-K)/Akt signal pathways in response to 6-OHDA insult and subsequent neuronal survival. Western blot revealed that 6-OHDA significantly increased the phosphorylation of ERK1/2 and Akt in mono-cultured SH-SY5Y cells. However, the increase in ERK1/2 in SH-SY5Y cells after co-cultured with astrocytes occurred as early as 3 h after 6-OHDA treatment in oppose to the increase after 12 h in monocultures. The phosphorylation of Akt in the co-cultured SH-SY5Y cells was much pronounced 3 h after 6-OHDA treatment compared with that in the mono-cultured cells. The anti-apoptotic protein bcl-2 was also increased in the co-cultured SH-SY5Y cells 3 h after treatment with 6-OHDA. Selective inhibitor of PI3-K/Akt signal pathway blocked the acquired resistance to 6-OHDA in SH-SY5Y cells following interaction with astrocytes. Inhibition of ERK1/2 signal pathway did not affect the cell survival. Our data suggest that PI3-K/Akt signal pathway, but not ERK1/2, is involved the acquired resistance in SH-SY5Y cells following cell-cell interaction with astrocytes against the neurotoxic 6-OHDA insult.
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PMID:Involvement of extracellular signal-regulated kinases 1/2 and (phosphoinositide 3-kinase)/Akt signal pathways in acquired resistance against neurotoxin of 6-hydroxydopamine in SH-SY5Y cells following cell-cell interaction with astrocytes. 1587 43

Flt1, an "fms-like tyrosine kinase" receptor, has been suggested to play an active role in vascular endothelial growth factor (VEGF)-mediated autocrine signaling of tumor growth and angiogenesis. Here, we used a neuroblastoma model to investigate the role of VEGF/Flt1 signaling in hypoxia-mediated tumor cell survival, drug resistance, and in vivo angiogenesis. SK-N-BE2, a highly malignant neuroblastoma cell line resistant to hypoxia-induced apoptosis expresses active Flt1 but lacks VEGFR2 expression. We found that 24-hour hypoxia (<0.1% O2) alone (no serum deprivation) showed sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) associated with bcl-2 up-regulation and resistance to etoposide-induced (5 mumol/L) apoptosis. Treatment with anti-VEGF and anti-Flt1 antibodies inhibited ERK1/2 activation, down-regulated bcl-2, and reversed the hypoxia-mediated drug resistance to etoposide. Similar results were obtained with U0126 and ursolic acid, specific and nonspecific inhibitors of ERK1/2, respectively. We confirmed the protective role of Flt1 receptor by small interfering RNA knockout and Flt1 overexpression studies. Subsequently, we found that inhibition of VEGF/Flt1 autocrine signaling led to reduced hypoxia-inducible factor-1alpha (HIF-1alpha) phosphorylation. Furthermore, the reduced phosphorylation was associated with down-regulation of basic fibroblast growth factor, a downstream target of the HIF-1alpha and VEGF pathways. Our findings suggested an expanded autocrine loop between VEGF/Flt1 signaling and HIF-1alpha. We investigated the angiogenic activity of the loop in an in vivo Matrigel plug assay. The hypoxia-treated conditioned medium induced a strong angiogenic response, as well as the cooption of surrounding vessels into the plugs; ursolic acid inhibited the angiogenesis process. We also found that three other Flt1-expressing neuroblastoma cell lines show hypoxia-mediated drug resistance to etoposide, melphalan, doxorubicin, and cyclophosphamide. Taken together, we conclude that a hypoxia-driven VEGF/Flt1 autocrine loop interacts with HIF-1alpha through a mitogen-activated protein kinase/ERK1/2 pathway in neuroblastoma. The interaction, in the form of an autocrine loop, is required for the hypoxia-driven cell survival, drug resistance, and angiogenesis in neuroblastoma.
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PMID:A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. 1610 78

Donepezil, rivastigmine, and galantamine are three drugs with acetylcholinesterase (AChE)-inhibiting activity that are currently being used to treat patients suffering from Alzheimer's disease. We have studied the neuroprotective effects of these drugs, in comparison with nicotine, on cell death caused by beta-amyloid (Abeta) and okadaic acid, two models that are relevant to Alzheimer's pathology, in the human neuroblastoma cell line SH-SY5Y. Galantamine and donepezil showed a U-shaped neuroprotective curve against okadaic acid toxicity; maximum protection was achieved at 0.3 microM galantamine and at 1 microM donepezil; at higher concentrations, protection was diminished. Rivastigmine showed a concentration-dependent effect; maximum protection was achieved at 3 microM. When apoptosis was induced by Abeta25-35, galantamine, donepezil, and rivastigmine showed maximum protection at the same concentrations: 0.3, 1, and 3 microM, respectively. Nicotine also afforded protection against Abeta- and okadaic acid-induced toxicity. The neuroprotective effects of galantamine, donepezil, and nicotine were reversed by the alpha7 nicotinic antagonist methyllycaconitine but not by the alpha4beta2 nicotinic antagonist dihydro-beta-erythroidine. The phosphoinositide 3-kinase (PI3K)-Akt blocker 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) reversed the protective effects of galantamine, donepezil, and nicotine but not that of rivastigmine. In contrast, the bcl-2 antagonist ethyl[2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate (HA 14-1) reversed the protective effects of the three AChE inhibitors and that of nicotine. Our results show that galantamine, donepezil, and rivastigmine afford neuroprotection through a mechanism that is likely unrelated to AChE inhibition. Such neuroprotection seemed to be linked to alpha7 nicotinic receptors and the PI3K-Akt pathway in the case of galantamine and donepezil but not for rivastigmine.
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PMID:Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells: role of nicotinic receptors. 1614 75

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in a variety of hematologic malignancies, but very little is known about its effects on solid tumors and especially on neuroblastoma cells that have self-differentiating characteristics. To demonstrate the growth inhibition induced in neuroblastoma cells (the SH-SY5Y and SK-N-AS cell line) and acute promyelocytic leukemia cells (HL-60) by arsenic trioxide (As2O3), the viable cell numbers were counted after trypan blue staining. Apoptosis was assessed by the cell morphology, by flow cytometry with annexin-V staining, and by Western blot analysis for the apoptosis-related proteins (bcl-2 and PARP). To decide the dose for the clinical application of As2O3, normal peripheral blood lymphocytes were also examined. The growth and survival of the SH-SY5Y and SK-N-AS cells were markedly inhibited by As2O3 treatment at a 3 microM concentration before the changes of the normal lymphocytes were observed. The apoptotic cells showed a shrunken cell nucleus, and an increase in the number and balloon-like swelling of the mitochondria at 72 h after the As2O3 was added. Apoptosis of the annexin-V-positive cell proportion in the neuroblastoma cell lines was increased with increasing the exposure time and the concentration of As2O3, just like the HL-60 cells. Bcl-2 downregulation and PARP degradation were also noted all the cell lines, but these changes were not statistically significant among the 3 cell lines. Taken together, these results indicate that As2O3 is an excellent candidate as a therapeutic agent for the treatment of neuroblastoma.
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PMID:Morphological and biochemical changes induced by arsenic trioxide in neuroblastoma cell lines. 1616 54

The beta amyloid (Abeta), the major protein component of brain senile plaques in Alzheimer's disease, is known to be directly responsible for the production of free radicals toxic to brain tissue and the redox state of Met-35 residue seems to play a particular and critical role in peptide's neurotoxic actions. In this study, we investigated, in human neuroblastoma cells (IMR-32), the relationship between the oxidative state of methionine, and both neurotoxic and pro-apoptotic actions induced by Abeta-peptide, comparing the effects of native peptide, in which the Met-35 is present in the reduced state, with those of a modified peptide with oxidized Met-35 (Abeta(1-42)(35Met-ox)), as well as an Abeta-derivative with Met-35 substituted with norleucine (Abeta(1-42)(35Nle)). The obtained results show that Abeta induces a time-dependent decrease in cell viability; Abeta(1-42)(35Met-ox) was significantly less potent, though inducing a remarkable decrease in cell viability compared to control. On the contrary, no toxic effects were observed after treatment with Abeta(1-42)(35Nle). Abeta-peptide as well as the amyloid modified peptide with oxidized Met-35 induced the pro-apoptotic gene bax over-expression after 24 h, whereas Abeta(1-42)(35Nle) had no effect. Conversely, bcl-2, an anti-apoptotic gene, became highly down-regulated by Abeta peptide treatment, in contrast to that evidenced by the Abeta(1-42)(35Met-ox) peptide. Finally, Abeta caused an increase in caspase-3 activity to be higher with respect to that shown by Abeta(1-42)(35Met-ox) while Abeta(1-42)(35Nle) had no effect. These results support the hypothesis that Abeta-induced neurotoxicity occurs via bax over-expression, bcl-2 down-regulation, and caspase-3 activation, first indicating that methionine 35 redox state may alter this cell death pathway.
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PMID:Alzheimer's amyloid beta-peptide (1-42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35. 1647 63

Retinoic acid (RA) has been shown to induce neuronal differentiation and/or apoptosis, and is widely used as a chemotherapeutic agent for treating the patients with neuroblastoma. However, the therapeutic effect of RA is still limited. To unveil the molecular mechanism(s) inducing differentiation and apoptosis in neuroblastoma cells, we compared CHP134 and NB-39-nu cell lines, in which all-trans-RA (ATRA) induces apoptosis, with LA-N-5 and RTBM1 cell lines, in which it induces neuronal differentiation. Here, we found that Bcl-2 was strongly downregulated in CHP134 and NB-39-nu cells, whereas it was abundantly expressed in LA-N-5 and RTBM1 cells. ATRA-mediated apoptosis in CHP134 and NB-39-nu cells was associated with a significant activation of caspase-9 and caspase-3 as well as cytoplasmic release of cytochrome c from mitochondria in a p53-independent manner. Enforced expression of Bcl-2 significantly inhibited ATRA-mediated apoptosis in CHP134 cells. In addition, treatment of RTBM1 cells with a Bcl-2 inhibitor, HA14-1, enhanced apoptotic response induced by ATRA. Of note, two out of 10 sporadic neuroblastomas expressed bcl-2 at undetectable levels and underwent cell death in response to ATRA in primary cultures. Thus, our present results suggest that overexpression of Bcl-2 is one of the key mechanisms to give neuroblastoma cells the resistance against ATRA-mediated apoptosis. This may provide a new therapeutic strategy against the ATRA-resistant and aggressive neuroblastomas by combining treatment with ATRA and a Bcl-2 inhibitor.
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PMID:Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma. 1656 81

Amyloid beta (1-42) peptide is considered responsible for the formation of senile plaques that accumulate in the brains of patients with Alzheimer's disease (AD). In the last years considerable attention has been focused on identifying natural food products, such as phytochemicals that prevent or almost retard the appearance of amyloid beta (1-42)-related neurotoxic effects. In this study, human neuroblastoma cells (IMR-32) was used as system model to evaluate the protective role of rhaponticin (3,3',5-trihydroxy-4'-methoxystilbene 3-O-d-glucoside) a stilbene glucoside extracted from rhubarb roots (Rhei rhizoma) and rhapontigenin, its aglycone metabolite, against amyloid beta (1-42)-dependent toxicity. The obtained results show that rhapontigenin maintains significant cell viability in a dose-dependent manner and it exerts a protective effect on mitochondrial functionality, as evidenced by mitochondrial oxygen consumption experiments. A similar behaviour, but to a lesser extent, has been shown by rhaponticin. The protective mechanism mediated by the two stilbenes could be related to their effect on bcl-2 gene family expression. Bax, a pro-apoptotic gene, resulted down-regulated by the treatment with rhaponticin and rhapontigenin compared with the results obtained in the presence of amyloid beta (1-42) peptide. Conversely, bcl-2, an anti-apoptotic gene, highly down-regulated by amyloid beta (1-42) treatment, resulted expressed in the presence of stilbenes similarly to that shown by control cells. The obtained results support the hypothesis that amyloid beta (1-42)-induced neurotoxicity occurs via bax over-expression, bcl-2 down-regulation, firstly indicating that rhaponticin and its aglycone moiety may alter this cell death pathway. Based on these studies, we suggest that rhaponticin and its main metabolite could be developed as agents for the management of AD.
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PMID:Protective effect of rhubarb derivatives on amyloid beta (1-42) peptide-induced apoptosis in IMR-32 cells: a case of nutrigenomic. 1711 25

Cholinergic cell lines were established by fusion of embryonic day 17 wild-type neurons from rat basal forebrain (BF) and upper brainstem (BS) with N18tg neuroblastoma cells. Isolated clones expressed choline acetyltransferase (ChAT) and neuronal nitric oxide synthase (nNOS) activities that were increased upon differentiation with retinoic acid. Clones from the BF expressed high levels of the tyrosine kinase type A (TrkA) receptor expression and activation of the mitogen-activated kinase ERK2 upon treatment with nerve growth factor. Like wild-type cholinergic populations, the six clones studied were variably resistant to nitric oxide (NO) excess from addition of S-nitroso-N-acetyl-D, L-penicillamine (SNAP). Of these, the BS2 clone exhibited resistance like in vivo BS cholinergic neurons, while the MS10 clone mimicked in vivo BF vulnerability. Apoptosis in response to NO excess was preceded by increases in mitochondrial responses bax/bcl-2 ratios, but cytochrome C was not released. Mitochondrial levels of apoptosis initiating factor (AIF) were either unchanged or increased, and only in MS clones was endonuclease G (EndoG) released. Microarray data indicated the existence of endoplasmic reticular (ER) stress and caspase-4 and caspase-12 were involved in the pathway to DNA fragmentation. The array data also indicated a survival role for mdm2, and its blockade rendered vulnerable the brainstem survivor clone BS2. Akt and ERK1/2 pathways were activated in response to NO and their blockade increased DNA fragmentation. Blockade of GSK-3 alpha/beta, a downstream target of Akt, reduced SNAP toxicity and this was more prominent in basal forebrain clones. We have identified two cholinergic cell lines useful for molecular studies of cholinergic vulnerability. We hypothesize that, in cholinergic neurons, control of ER stress signaling may be a major factor in differential vulnerability.
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PMID:Establishment of cholinergic neuron-like cell lines with differential vulnerability to nitrosative stress. 1750 6

Morphoproteomic analysis reveals the constitutive activation of the mTOR, ERK, and NF-kappaB pathways in high risk neuroblastoma (HRN) cases as evidenced by (a) collective commonalities of: phosphorylated (p)-mTOR, p70S6K, ERK 1/2, and NF-kappaBp65 protein analytes using phosphospecific probes directed against sites of activation; (b) nuclear translocation of p-p70S6K, p-ERK 1/2, and p-NF-kappaBp65; and (c) correlative expression of the S phase-associated kinase Skp-2 (at a relatively high percentage in tumoral nuclei) and of the anti-apoptotic protein bcl-2. Based on a review of the literature, these preliminary observations appear to be the first morphoproteomic study on primary neuroblastomas.
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PMID:Morphoproteomic confirmation of constitutively activated mTOR, ERK, and NF-kappaB pathways in high risk neuro-blastoma, with cell cycle and protein analyte correlates. 1752 69

We examined 111 cases of neuroblastoma (NB), searching for how NB relates to apoptotic control and other prognostic factors. Immunohistochemistry using avidin-biotin-peroxidase was carried out for bcl-2 and p53 proteins. Apoptosis was analyzed by in situ detection of chromosomal breakdown. DNA ladders were detected by electrophoresis and amplification of MYCN was carried out by PCR and Southern blot. Statistical analyses were performed with Pearson's chi2 and Kruskal-Wallis tests and Cox's regression. We found expression of bcl-2 protein mainly in cases of neuroblastoma without differentiation and in stages 3 and 4. Expression of p53 protein showed a correlation with bcl-2 and the apoptotic phenomenon; apoptosis was found mainly in favorable cases. Multivariate analysis showed bcl-2 protein expression to be the most independent risk factor. The study of apoptosis could be important for the design of therapies to treat neuroblastoma.
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PMID:Apoptosis in peripheral neuroblastic tumors. Immunohistochemical expression of bcl-2 and p53 is related to DNA fragmentation. 1770 16


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