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)

In vivo studies show (a) that early exposure to ethanol depletes neurons in the central nervous system (CNS) and (b) that a primary target of ethanol in the developing nervous system is proliferating neuronal precursors. We used a neuronal cell line (B 104 neuroblastoma cells) as an in vitro model for the effects of ethanol on the proliferation of neuronal precursors to test the hypothesis that ethanol interferes with growth factor-regulated proliferation of neuron-like precursors. The effects of ethanol on the mitogenic activity of two growth factors, basic fibroblast growth factor (bFGF) and platelet-derived growth factor AA and BB (PDGF-AA and PDGF-BB), were examined. Cell proliferation was monitored by tracing the change in the numbers of cultured cells over 4-5 days and in the cell cycle kinetics was determined using a cumulative labeling technique with bromodeoxyuridine (BrdU). Western immunoblots and immunohistochemical preparations show that B104 cells expressed the high affinity receptors for bFGF, PDGF-AA and PDGF-BB. The three growth factors were potent mitogens for the B104 cells; they promoted an increase in cell number even when the cells were grown in serum-free medium. Ethanol depressed the bFGF-, PDGF-AA- and PDGF-BB-mediated cell proliferation without altering the incidence of cell death. These changes in proliferation were concentration-dependent; at a concentration of 100 mg/dl, ethanol partially, but significantly inhibited growth factor-stimulated proliferation and higher ethanol concentrations (400 mg/dl or more) completely abolished growth factor-regulated cell proliferation. The effects of ethanol on cell growth were a result of ethanol-induced changes in growth factor-regulated cell cycle kinetics, principally the total length of the cell cycle and the fraction of the population that was actively cycling (the growth fraction). Ethanol completely negated the action of bFGF, but only partially blocked PDGF-promoted cycling activity. Thus, B104 cells are a suitable model for studying the effects of ethanol on neuronal proliferation. The blockage of bFGF- and PDGF-mediated cell proliferation by ethanol supports the hypothesis that growth factors are a target of ethanol neurotoxicity. Furthermore, the differential actions and effects of ethanol on the two growth factors mirror effects observed in vivo.
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PMID:Basic fibroblast growth factor- and platelet-derived growth factor-mediated cell proliferation in B104 neuroblastoma cells: effect of ethanol on cell cycle kinetics. 937 13

The main physiological role of somatostatin (SST) is the control of hormone secretion. Recently, SST has been shown to exert antiproliferative effects on some human tumors via both direct and indirect mechanisms. We have previously found that in the human neuroblastoma cell line SY5Y the SST analogue lanreotide (BIM 23014) inhibited serum-stimulated cell proliferation and MAP kinase activity. Here, we examine the effect of SST on PDGF-induced Ras activation. We found that SST suppressed PDGF-induced Ras activation in a pertussis toxin (PTx)-independent and peroxovanadate-dependent manner. Ras-specific GTPase activating protein (GAP) activities were not altered by SST treatment. On the contrary, PDGF-induced PDGF receptor phosphorylation was decreased by SST in a PTx-independent, peroxovanadate-dependent manner, likely accounting for the SST-mediated inhibition of PDGF-induced Ras activation.
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PMID:Somatostatin inhibits PDGF-stimulated Ras activation in human neuroblastoma cells. 1050 18

Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by tumor cells. Neuroblastoma (NB) is a common pediatric tumor of neural crest origin, which is biologically and clinically heterogeneous. Increased tumor vascular index correlates with poor outcome of NB. To determine which angiogenic factors contribute to NB angiogenesis and thereby support tumor progression, we examined the expression of eight angiogenic factors [vascular endothelial growth factor (VEGF), VEGF-B, VEGF-C, basic fibroblast growth factor, angiopoietin (Ang)-1, Ang-2, transforming growth factor alpha, and platelet-derived growth factor (PDGF)] by semiquantitative RT-PCR in 37 NB primary tumors and in 22 NB cell lines. We also analyzed the relationship between angiogenic factor expression and clinicopathological factors as well as patient survival. All eight angiogenic factors examined were expressed at various levels in NB cell lines and tumors, suggesting their involvement in NB angiogenesis. The expression levels of most angiogenic factors were correlated with each other, suggesting their synergy in regulating the angiogenic process. Significantly higher expression levels of VEGF, VEGF-B, VEGF-C, basic fibroblast growth factor, Ang-2, transforming growth factor alpha, and PDGF-A (P < 0.0001-0.026) were found in advanced-stage tumors (stages 3 and 4) compared with low-stage tumors (stages 1, 2, and 4S). Expression of PDGF-A was significantly associated with patient survival (P = 0.04). The redundancy in angiogenic factor expression suggests that inhibition of VEGF bioactivity alone might not be a sufficient approach for antiangiogenic therapy of human NB.
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PMID:High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. 1081 14

The platelet-derived growth factor receptor (PDGFR) is a receptor tyrosine kinase overexpressed in a subset of solid tumors and therefore is the target of drugs inhibiting this function such as imatinib mesylate (Gleevec). Thus far, drug therapy has played a limited role in the treatment of localized prostate cancer (PCa). This study characterizes PDGFR-beta expression in a wide spectrum of PCa samples to provide empirical data as part of a rational treatment strategy. A survey of five published prostate expression array studies, including 100 clinically localized PCa, did not identify tumors with increased PDGFR-beta expression level. Protein expression of PDGFR-beta, as determined by immunohistochemistry, revealed 5% of clinically localized PCa and 16% of metastatic PCa cases to show moderate or strong expression. To develop a strategy to detect patients most likely to profit from Gleevec treatment, we analyzed cDNA expression array data from 10,000 transcripts for PDGFR-beta expression and divided tumors in groups based on PDGFR-beta expression level. Performing a supervised analysis to identify potential comarkers of PDGFR-beta in PCa, we identified a set of genes whose expression was associated with PDGFR-beta status including early growth response 1 (Egr1), an upstream effector of PDGF (4.2-fold upregulation), alpha-methylacyl-CoA racemase, as well as v-Maf and neuroblastoma suppressor of tumorigenicity (both with a 2.2-fold downregulation). Taken together, this study suggests that only a small subset of PCas may be amenable to tyrosine kinase inhibitors specific for PDGFR.
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PMID:Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications with tyrosine kinase inhibitors. 1554 58

Several transmembrane molecules are cleaved at juxtamembrane extracellular sites leading to shedding of ectodomains. We analysed shedding of members of the Vps10p-D (Vps10p domain; where Vps is vacuolar protein sorting) family of neuronal type-I receptors with partially overlapping functions, and additional proteolytic events initiated by the shedding. When transfected into CHO (Chinese-hamster ovary) cells (CHO-K1), sorCS1a-sorCS1c isoforms were shed at high rates (approximately 0.61% x min(-1)) that were increased approx. 3-fold upon stimulation with phorbol ester. sorCS1c identified in the cultured neuroblastoma cell line SH-SY5Y was shed similarly. In CHO-K1 transfectants, constitutive and stimulated shedding of sorCS3 also occurred at high rates (0.29% and 1.03% x min(-1)). By comparison, constitutive and stimulated shedding of sorLA occurred at somewhat lower rates (0.07% and 0.48% x min(-1)), whereas sorCS2 and sortilin were shed at very low rates even when stimulated (approximately 0.01% x min(-1)). Except for sorCS2, shedding of the receptors was dramatically reduced in mutant CHO cells (CHO-M2) devoid of active TACE (tumour necrosis factor alpha-converting enzyme), demonstrating that this enzyme accounts for most sheddase activity. The release of sorCS1 and sorLA ectodomains initiated rapid cleavage of the membrane-tethered C-terminal stubs that accumulated only in the presence of gamma-secretase inhibitors. Purified shed sorLA bound several ligands similarly to the entire luminal domain of the receptor, including PDGF-BB (platelet-derived growth factor-BB) and amyloid-beta precursor protein. In addition, PDGF-BB also bound to the luminal domains of sorCS1 and sorCS3. The results suggest that ectodomains shed from a subset of Vps10p-D receptors can function as carrier proteins.
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PMID:Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members. 1639 39

The platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase, implicated in the development and progression of different tumors, including gliomas. Chemoresistance is a common feature of malignant gliomas. Since receptor tyrosine kinases contribute to chemoresistance in tumors, we addressed whether PDGFR signaling might confer selective growth advantage to chemoresistant cells. The effects of the PDGFR inhibitor STI571 on proliferation and PDGFR signaling were compared in chemosensitive and cisplatin-selected, chemoresistant sublines derived from glioma and from two other PDGFR-expressing tumors (ovarian carcinoma and neuroblastoma). The chemoresistant glioma U87/Pt cells were twofold more sensitive to STI571 growth-inhibitory effects than the chemosensitive U87 cells, and two- to threefold more sensitive than five unrelated glioma cell lines. The other two paired cell lines were equally responsive. Sensitization of U87/Pt cells correlated with upregulation of the PDGF-B isoform and with PDGF-BB-induced Akt overactivation, which was prevented by STI571. STI571 specifically inhibited PDGF-BB-, but not PDGF-AA- or stem cell factor-mediated signaling. In serum-containing medium, STI571 decreased phospho-Akt in U87/Pt cells, but not in U87, while activating extracellular signal-regulated kinase (Erk) in both. STI571 antiproliferative effects were partially reverted by constitutively active Akt. Cotreatment with inhibitors of phosphatidylinositol 3'-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK) resulted in enhanced growth inhibition in glioma cells. Our results suggest that increased PDGF-BB signaling may sensitize chemoresistant glioma cells to STI571, suggesting a therapeutic potential for STI571 in patients with malignant gliomas refractory to chemotherapy. Simultaneous blockade of PDGFR and PI3K or Erk pathway may enhance therapeutic targeting in gliomas.
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PMID:Increased sensitivity to the platelet-derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF-BB-mediated signaling and STI571-induced Akt inactivation. 1657 5

PDGF acts as an autocrine and paracrine factor in certain tumors through upregulation of the PDGF beta-receptor expression. In order to elucidate the control mechanism for the receptor expression, we have isolated an enhancer from two P1 clones that together contain a 102 kb NotI region covering the entire human PDGFRB gene. They were partially digested with TspI and cloned into the PDGFRB enhancer trap vector to make a library for identification of enhancers. The digested DNA containing enhancer was identified by expression of GFP when transfected in PDGF beta-receptor expressing cells. One of the enhancer clones was further examined by making several deletion mutants in a luciferase vector. This enhancer was most active in neuroblastoma cells, IMR32 and BE2, but less active in hemangioma and in smooth muscle cell lines. Chip assay revealed that SP1, AP2, and GATA2 bound the enhancer in BE2 cells. Their interaction occurred dependently of the cell cycle and synchronously with their binding to the promoter. Transfection of GATA2 alone or with Ets, which binds adjacent to GATA, resulted in differentiation of BE2 cells in parallel with increased PDGF beta-receptor expression. Furthermore, over-expression of the PDGF beta-receptor in BE2 cells induced neurite extension.
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PMID:Activity of a novel PDGF beta-receptor enhancer during the cell cycle and upon differentiation of neuroblastoma. 1662 90

Imatinib is currently in early clinical trials as targeted therapy for relapsed neuroblastomas and other childhood solid tumors expressing platelet-derived growth factor receptors (PDGFR) or c-Kit. Short-term treatment with imatinib in clinically achievable concentrations is ineffective in neuroblastoma in vitro. However, clinically, imatinib is administered daily over long time periods. The effects of combining imatinib with chemotherapy in neuroblastoma are unknown. Here, a panel of neuroblastoma cell lines (n = 5) were studied, representing tumors with different biological (MYCN-amplification +/-) and clinical (drug resistance) features. Using a protracted low-dose treatment schedule (1-3 weeks; 0.5-5microM) imatinib dose-dependently inhibited proliferation and clonogenic survival for all tested cell lines with IC50 <2.5microM. In contrast, short-term treatment (<96 hrs) was ineffective. Low-dose imatinib was synergistic in combination with doxorubicin and caused increased G2/M- and S-phase arrest and apoptosis as evidenced by enhanced caspase-3 activation and sub-G1 DNA accumulation. A significant but less pronounced effect was observed when imatinib was combined with etoposide or vincristine, as opposed to cisplatin, melphalan, or irinotecan. All cell lines expressed PDGFRbeta, whereas no protein expression of PDGFRalpha was detected in MYCN amplified cell lines. PDGF-BB caused PDGFRbeta phosphorylation and partially rescued neuroblastoma cells from doxorubicin-induced apoptosis, in an imatinib-sensitive manner. In vivo, treatment with imatinib in combination with doxorubicin induced a significant growth inhibition of established neuroblastoma xenografts. These findings suggest clinical testing of imatinib in combination with selected chemotherapeutic drugs, in particular doxorubicin, in children with high-risk neuroblastoma.
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PMID:Metronomic scheduling of imatinib abrogates clonogenicity of neuroblastoma cells and enhances their susceptibility to selected chemotherapeutic drugs in vitro and in vivo. 1905 99

The neuropathological abnormalities of human immunodeficiency virus (HIV)-1 patients abusing illicit drugs suggest extensive interactions between the two agents, thereby leading to increased rate of progression to neurodegeneration. The role of HIV-1 transactivating protein, Tat has been elucidated in mediating neuronal damage via apoptosis, a hallmark of HIV-associated dementia (HAD), however the underlying mechanisms involved in enhanced neurodegeneration by illicit drugs remain elusive. In this study, we demonstrated that morphine enhances HIV-Tat induced toxicity in human neurons and neuroblastoma cells. Enhanced toxicity by Tat and morphine was accompanied by increased numbers of TUNEL positive apoptotic neurons, elevated caspase-3 levels and decreased ratio of anti- and pro-apoptotic proteins, Bcl2/Bax. Tat and morphine together elicited high levels of reactive oxygen species that were NADPH dependent. Significant alterations in mitochondrial membrane homeostasis were also observed with co-exposure of these agents. Extensive studies of mitogen activated protein kinase (MAPK) signaling pathways revealed the involvement of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways in enhanced toxicity of Tat and morphine. In addition to this, we found that pre-treatment of cells with platelet derived growth factor (PDGF-BB) protected neurons from HIV-Tat and morphine induced damage. PDGF-BB alleviated ROS production, maintained mitochondrial membrane potential, decreased caspase-3 activation and hence protected the cells from undergoing apoptosis. PDGF-BB mediated protection against Tat and morphine involved the phosphatidylinositol-3 kinase (PI3K) pathway, as specific inhibitor of PI3K abrogated the protection conferred by PDGF-BB. This study demonstrates the mechanism of enhanced toxicity in human neurons subjected to co-exposure of HIV protein Tat and morphine, thus implying its importance in HIV positive drug abusers, where damage to the brain is reported to be more severe than non-drug abusers. We have also showed for the first time that PDGF-BB can protect against simultaneous exposure of Tat and morphine, strengthening its role as a neuroprotective agent that could be considered for therapeutic intervention.
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PMID:A growth factor attenuates HIV-1 Tat and morphine induced damage to human neurons: implication in HIV/AIDS-drug abuse cases. 2148 69

The conditioned medium from B104 neuroblastoma cells (B104CM) induces neural stem cells (NSCs) to differentiate into OPCs in vitro, which indicates that certain factor(s) contained within the B104CM must give instructional signals that direct OPC differentiation of NSCs. However, the OPC-inductive factor(s) present within the B104CM has not been well identified yet. Platelet-derived growth factor AA (PDGF-AA) was not only known to be a potent mitogen for OPC proliferation but also to act as a regulator of oligodendrocyte differentiation from multipotent embryonic NSCs. This raises the possibility that B104CM induces OPC differentiation of NSCs through secretion of PDGF-AA. In the present study, we detected the expression of PDGF-AA mRNA in B104 cells and the high level of PDGF-AA protein in B104CM. Most importantly, B104CM-induced OPC differentiation of NSCs could be completely blocked by AG1295, a specific inhibitor of PDGFR signal pathway, suggesting that the PDGF-AA in B104CM is the key factor that induces NSCs to differentiate into OPCs. Moreover, such B104CM-induced OPC differentiation appears to be mediated by the extracellular signal-regulated kinases 1 and 2 (Erk1/2), phosphatidylinositol-3 kinase (PI3K), and p38 signal pathway because B104CM elicited the activation of Erk1/2, PI3K, and p38, which could be markedly blocked by U0126, LY294002, and SB203580, several specific inhibitors of these signal pathway, respectively. These inhibitors also abolished OPC differentiation of NSCs completely. Together our study suggests that PDGF-AA contained in B104CM is the key regulating molecule that instructs OPC differentiation from embryonic NSCs through the activation of Erk, PI3K, and p38 signal pathway in vitro.
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PMID:PDGF-AA mediates B104CM-induced oligodendrocyte precursor cell differentiation of embryonic neural stem cells through Erk, PI3K, and p38 signaling. 2195 9


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