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)

In the present study we investigated the signal transduction pathways leading to the activation of extracellular signal-regulated kinase (ERK) by opioid or cannabinoid drugs, when their receptors are coexpressed in the same cell-type. In N18TG2 neuroblastoma cells, the opioid agonist etorphine and the cannabinoid agonist CP-55940 induced the phosphorylation of ERK by a similar mechanism that involved activation of delta-opioid receptors or CB1 cannabinoid receptors coupled to Gi/Go proteins, matrix metalloproteases, vascular endothelial growth factor (VEGF) receptors and MAPK/ERK kinase (MEK). In HEK-293 cells, these two drugs induced the phosphorylation of ERK by separate mechanisms. While CP-55940 activated ERK by transactivation of VEGFRs, similar to its effect in N18TG2 cells, the opioid agonist etorphine activated ERK by a mechanism that did not involve transactivation of a receptor tyrosine kinase. Interestingly, the activation of ERK by etorphine was resistant to the inhibition of MEK, suggesting the possible existence of a novel, undescribed yet mechanism for the activation of ERK by opioids. This mechanism was found to be specific to etorphine, as activation of ERK by the micro-opioid receptor (MOR) agonist DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol] enkephalin) was mediated by MEK in these cells, suggesting that etorphine and DAMGO activate distinct, ligand-specific, conformations of MOR. The characterization of cannabinoid- and opioid-induced ERK activation in these two cell-lines enables future studies into possible interactions between these two groups of drugs at the level of MAPK signaling.
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PMID:Modulation of extracellular signal-regulated kinase (ERK) by opioid and cannabinoid receptors that are expressed in the same cell. 1806 91

Evidence suggests that vascular endothelial growth factor (VEGF) mediates neuroprotection to prevent an apoptotic cell death. The p38 mitogen-activated protein kinase (MAPK) pathway is implicated as an important mediator of neuronal apoptosis but its role in VEGF-mediated neuroprotection is unclear. Herein, we show that treatments with the p38 MAPK inhibitor, SB202190, enhanced VEGF-mediated survival in serum deprived SK-N-SH neuroblastoma cells by decreasing caspase-3/7 activation while increasing the phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and Akt signaled through the VEGF receptor, VEGFR2. A blockade of VEGFR2 signaling with a selective inhibitor, SU1498 or gene silencing with VEGFR2 siRNA in SB202190 treated cells abrogated this prosurvival response and induced high activation levels of caspase-3/7. These findings suggested that the protection elicited by p38 MAPK inhibition in serum starved cells was dependent on a functional VEGF/VEGFR2 pathway. However, p38 MAPK inhibition attenuated caspase-3 cleavage in SU1498/SB202190 treated cells, indicating that p38 MAPK and caspase-3 only contributed in part to the total levels of caspase-3/7 induced by VEGFR2 inhibition. Pretreatments with the pan caspase inhibitor, z-VAD-fmk, prevented the apoptosis induced by VEGFR2 inhibition and promoted survival in serum starved cells irrespective of p38 MAPK inhibition. Collectively, our findings suggest that p38 MAPK exerts a negative effect on VEGF-mediated signaling through VEGFR2 in serum starved neuroblastoma cells. Furthermore, VEGF signals protection against a caspase-mediated cell death that is regulated by p38 MAPK-dependent and -independent mechanisms.
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PMID:p38 MAPK as a negative regulator of VEGF/VEGFR2 signaling pathway in serum deprived human SK-N-SH neuroblastoma cells. 1817 12

Among children with relapsed or refractory neuroblastoma, the prognosis is poor and novel therapeutic strategies are needed to improve long-term survival. As with other solid tumors, high vascular density within neuroblastoma is associated with advanced disease, and therapeutic regimens directed against the tumor vasculature may provide clinical benefit. The receptor tyrosine kinase RET is widely expressed in neuroblastoma and is known to activate key signal transduction pathways involved in tumor cell survival and progression including Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt. We investigated the effect of dual targeting of tumor cells and tumor endothelium with ZD6474, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor 2, epidermal growth factor receptor, and RET. ZD6474 inhibited the phosphorylation of RET in neuroblastoma cells and had a direct effect on tumor cell viability in seven neuroblastoma cell lines. In a human neuroblastoma xenograft model, ZD6474 inhibited tumor growth by 85% compared with treatment with vehicle alone. In contrast, no significant inhibition of tumor growth was observed after treatment with bevacizumab, an antihuman VEGF monoclonal antibody, or the epidermal growth factor receptor inhibitor erlotinib, either alone or in combination. Immunohistochemical analysis showed that ZD6474 treatment led to an increase in endothelial cell apoptosis along with inhibition of VEGF receptor-2 activation on tumor endothelium. In conclusion, dual targeting of tumor cells, potentially through RET inhibition, and tumor vasculature with ZD6474 leads to potent antitumor effects. This approach merits further investigation for patients with neuroblastoma.
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PMID:Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium. 1824 71

Angiogenesis in neuroblastoma (NB) correlates with increased expression of vascular endothelial growth factor (VEGF) and a worse clinical outcome. Other cellular markers, such as Akt activation and MYCN amplification, are also associated with poor prognosis in NB; therefore, we sought to determine the role of N-myc in the regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/VEGF pathway. PI3K inhibition, using small-molecule inhibitors or phosphatase and tensin homolog adenovirus, led to decreased levels of VEGF mRNA and/or protein by reducing phosphorylation of Akt and mammalian target of rapamycin (mTOR), and attenuating hypoxia-inducible factor 1alpha expression. Moreover, PI3K inhibition decreased levels of N-myc expression in MYCN-amplified cells. To further clarify the importance of N-myc as a target of PI3K in VEGF regulation, we inhibited N-myc expression by siRNA transfection. MYCN siRNA significantly blocked VEGF secretion, irrespective of serum conditions, in MYCN-amplified NB cells; this effect was enhanced when combined with rapamycin, an mTOR inhibitor. Interestingly, in cells with low-N-myc expression, MYCN siRNA reduction of VEGF secretion was only effective with MYCN overexpression or insulin-like growth factor-1 stimulation. Our results show that N-myc plays an important role in the PI3K-mediated VEGF regulation in NB cells. Targeting MYCN, as a novel effector of PI3K-mediated angiogenesis, has significant potential for the treatment of highly vascularized, malignant NB.
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PMID:N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma. 1827 68

In the present study, irinotecan (CPT-11) was highly effective not only against the chemosensitive neuroblastoma (NB) xenografts SK-N-ASnu and TNB9, but also against the multidrug-resistant NB xenograft TS-N-2nu. SK-N-ASnu and TNB9 were significantly more responsive to low-dose daily CPT-11 treatment than to intermittent administration of one-third of the median lethal dose. For TS-N-2nu, there was no significant difference in tumor growth inhibition between the two treatment schedules. Treatment with CPT-11 alone could not completely abolish tumor growth in mice. For TNB9, tumor regrowth seemed to result from an inability to regress host vessels in the stroma during treatment and an inability to suppress host-derived vascular endothelial growth factor (VEGF) expression throughout therapy. In the multidrug-resistant TS-N-2nu, VEGF was not suppressed by low-dose therapy with CPT-11, and neurofilament-positive tumor cells escaped from apoptosis and were growth arrested at G(0)/G(1) phase. These findings suggest a mechanism for the incomplete responsiveness of TS-N-2nu to CPT-11. Our data demonstrate that diminished VEGF gene and protein expression is closely correlated with tumor growth inhibition and inhibition of angiogenesis by CPT-11 in NB xenografts. Our results further suggest that a persistent blocker of stroma-derived VEGF will need to be combined with CPT-11 to completely inhibit the growth of chemosensitive NB, and that administration of CPT-11 at higher doses will be required to inhibit the growth of multidrug-resistant NB.
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PMID:Vascular endothelial growth factor expression is closely related to irinotecan-mediated inhibition of tumor growth and angiogenesis in neuroblastoma xenografts. 1838 33

Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor-induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy.
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PMID:A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. 1855 19

The purpose of the study was to investigate the antitumor effects of Isatin and the related mechanism. Human neuroblastoma cells (SH-SY5Y) were exposed to Isatin at different concentrations for 48 h. Apoptotic features were demonstrated by means of nuclei staining with Hoechst 33258 and flow cytometry with propidium iodide (PI). Expressions of Bcl-2, Bax and vascular endothelial growth factor (VEGF) mRNA were analyzed via RT-PCR. Expressions of Bcl-2, Bax proteins and phosphorylated extracellular signal regulated protein kinases (ERKs, p42/p44) were analyzed via Western blot. Activation of caspase-3 was assayed by flow cytometry with anti-active caspase-3-McAb-PE. VEGF protein was determined by ELISA kits. And the results showed that apoptosis of SH-SY5Y cells were induced by Isatin in a dose-dependent manner. Expressions of Bcl-2, VEGF mRNA and Bcl-2, VEGF proteins were down-regulated, while expressions of Bax mRNA and Bax protein were not changed obviously. Expression of phosphorylated ERKs decreased, but the level of activated caspase-3 increased after treatment of Isatin. These results suggest that Isatin promotes the apoptosis of neuroblastoma cells, therefore, it might be a potential candidate for the treatment of neuroblastoma.
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PMID:Antitumor effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism. 1856 13

Neuroblastoma produce angiogenic peptides, and the extent of angiogenesis correlates with tumor progression and poor clinical outcome. Hence, angiogenic factor inhibition represents an important therapeutic option. One of the major drives to tumor angiogenesis is hypoxia, a decrease in oxygen tension that characterizes the tumor microenvironment. We investigated the effects of the topoisomerase I inhibitor, topotecan, on vascular endothelial growth factor (VEGF) induction by hypoxia in advanced-stage human neuroblastoma cells. Topotecan counteracted hypoxic induction of VEGF and decreased angiogenic activity of conditioned medium from hypoxic cultures in vivo in the chick chorioallantoic membrane. Promoter-driven reporter studies showed the role of both hypoxia-inducible factor (HIF)-1alpha and -2alpha in VEGF transcription activation by hypoxia, because (a) overexpression of either protein by cotransfection with expression vectors resulted in VEGF promoter transactivation, which was abrogated by mutation in the HIF-binding site, and (b) targeted knockdown of HIF-1alpha/2alpha by RNA interference inhibited hypoxia-stimulated VEGF transcriptional activity and protein secretion. Topotecan-inhibitory effects on VEGF induction by hypoxia were mediated through suppression of both HIF-1alpha and HIF-2alpha protein accumulation and transactivation properties, which was specific and required ongoing RNA transcription. A similar pattern of results was obtained in cells treated with the hypoxia-mimetic agent, desferrioxamine. These data provide the first evidence that topotecan is a potent inhibitor of HIF-1alpha and HIF-2alpha subunits in hypoxic neuroblastoma cells, leading to decreased VEGF expression and angiogenic activity. An important clinical implication of these findings is that therapies targeted to the HIF pathway have the potential to inhibit neuroblastoma angiogenesis and growth.
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PMID:Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1alpha and -2alpha. 1864 7

The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through IGF-I receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-II binding and by inducing cell surface receptor down-regulation via internalization and degradation, with the extracellular and intracellular domains of IGF-IR being differentially affected by the proteasomal and lysosomal inhibitors. In vitro, h10H5 exhibits antiproliferative effects on cancer cell lines. In vivo, h10H5 shows single-agent antitumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models and even greater efficacy in combination with the chemotherapeutic agent docetaxel or an anti-vascular endothelial growth factor antibody. Antitumor activity of h10H5 is associated with decreased AKT activation and glucose uptake and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors and furthermore illustrate a new method of monitoring its activity noninvasively in vivo via 2-fluoro-2-deoxy-d-glucose-positron emission tomography imaging.
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PMID:Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake. 1879 Jul 43

Human peripheral gammadelta-T-cells are able to induce cytolysis of neuroblastoma (Nb) tumor cells. Besides innate effector functions against infected cells and tumors, gammadelta-T-cells are involved in T-helper 1/T-helper 2 (TH1/TH2) differentiation of alphabeta-T-cells. However, as different gammadelta-T-cell subsets vary considerably in their functional properties, the aim of the present study was to define repertoires of cytokines, chemokines, and angiogenic factors of in vitro expanded Vdelta1+ and Vdelta2+ T cells in response to Nb. After short-term culture, both subsets released TH1 [interleukin (IL)-2, interferon (IFN)-gamma, IL-12, tumor necrosis factor (TNF)-alpha, TNF-beta)] and TH2 cytokines (IL-4, -5, -6, -10, -13, Vdelta1 also transforming growth factor (TGF)-beta, chemokines (I-309, monocyte chemotactic protein (MCP)-1-3, regulated upon activation, normal T-cell expressed and secreted), ILs (IL-1, -8, -15), cytokines (leptin) as well as angiogenic growth factors [angiogenin (ANG), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), Insulin-like growth factor (IGF)-I]. These molecules were expressed at higher levels in Vdelta2+ than Vdelta1+ T cells. Nb challenge changed protein expression. TH2 cytokine and IFN-gamma release was blocked in both gammadelta-T-cell subsets. In Vdelta2 gammadelta-T-cells, TH1 cytokines were down-regulated and tumor growth-promoting factors (ANG, VEGF, EGF, and IGF-I) were strongly up-regulated. In contrast, Vdelta1+ gammadelta-T-cells stopped the release of tumor-supportive factors and tolerogenic TGF-beta, and strongly up-regulated TNF-alpha, TNF-beta, MCP-1 and -2 and maintained their IL-2 production. In summary, our data show that after being challenged with Nb cells, propagated Vdelta1+ rather than Vdelta2+ T cells support antitumor responses by secretion of proinflammatory cytokines. Furthermore, in contrast to other cell types, Vdelta1+ T cells do not sustain a growth-promoting or tolerogenic microenvironment. These data make Vdelta1+ T cells an ideal candidate for upcoming immunotherapy trials in Nb.
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PMID:Immune response of human propagated gammadelta-T-cells to neuroblastoma recommend the Vdelta1+ subset for gammadelta-T-cell-based immunotherapy. 1883 98

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