oxadiazoles has been researched along with Neuroblastoma* in 14 studies
1 review(s) available for oxadiazoles and Neuroblastoma
1 trial(s) available for oxadiazoles and Neuroblastoma
13 other study(ies) available for oxadiazoles and Neuroblastoma
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Bioisosteric replacement based on 1,2,4-oxadiazoles in the discovery of 1H-indazole-bearing neuroprotective MAO B inhibitors.
Following a hybridization strategy, a series of 5-substituted-1H-indazoles were designed and evaluated in vitro as inhibitors of human monoamine oxidase (hMAO) A and B. Among structural modifications, the bioisostere-based introduction of 1,2,4-oxadiazole ring returned the most potent and selective human MAO B inhibitor (compound 20, IC Topics: Humans; Hydrogen Peroxide; Indazoles; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroblastoma; Neuroprotection; Oxadiazoles; Structure-Activity Relationship | 2023 |
Synthesis and Bioactivity Evaluation of a Novel 1,2,4-Oxadiazole Derivative in vitro and in 3×Tg Mice.
Alzheimer's disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, β-amyloid (Aβ) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy.. The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study.. Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). H. wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aβ clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected.. wyc-7-20 was potent in AD therapy. Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Humans; Hydrogen Peroxide; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; Neurodegenerative Diseases; Neuroprotective Agents; Oxadiazoles; Reactive Oxygen Species; tau Proteins | 2022 |
Inhibition of γ-Secretase Leads to an Increase in Presenilin-1.
γ-Secretase inhibitors (GSIs) are potential therapeutic agents for Alzheimer's disease (AD); however, trials have proven disappointing. We addressed the possibility that γ-secretase inhibition can provoke a rebound effect, elevating the levels of the catalytic γ-secretase subunit, presenilin-1 (PS1). Acute treatment of SH-SY5Y cells with the GSI LY-374973 (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, DAPT) augments PS1, in parallel with increases in other γ-secretase subunits nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1, yet with no increase in messenger RNA expression. Over-expression of the C-terminal fragment (CTF) of APP, C99, also triggered an increase in PS1. Similar increases in PS1 were evident in primary neurons treated repeatedly (4 days) with DAPT or with the GSI BMS-708163 (avagacestat). Likewise, rats examined after 21 days administered with avagacestat (40 mg/kg/day) had more brain PS1. Sustained γ-secretase inhibition did not exert a long-term effect on PS1 activity, evident through the decrease in CTFs of APP and ApoER2. Prolonged avagacestat treatment of rats produced a subtle impairment in anxiety-like behavior. The rebound increase in PS1 in response to GSIs must be taken into consideration for future drug development. Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Behavior, Animal; Cell Line, Tumor; Dipeptides; Humans; Male; Mice; Neuroblastoma; Neurons; Oxadiazoles; Presenilin-1; Rats; Rats, Wistar; Substrate Specificity; Sulfonamides | 2018 |
Targeting of the MYCN protein with small molecule c-MYC inhibitors.
Members of the MYC family are the most frequently deregulated oncogenes in human cancer and are often correlated with aggressive disease and/or poorly differentiated tumors. Since patients with MYCN-amplified neuroblastoma have a poor prognosis, targeting MYCN using small molecule inhibitors could represent a promising therapeutic approach. We have previously demonstrated that the small molecule 10058-F4, known to bind to the c-MYC bHLHZip dimerization domain and inhibiting the c-MYC/MAX interaction, also interferes with the MYCN/MAX dimerization in vitro and imparts anti-tumorigenic effects in neuroblastoma tumor models with MYCN overexpression. Our previous work also revealed that MYCN-inhibition leads to mitochondrial dysfunction resulting in accumulation of lipid droplets in neuroblastoma cells. To expand our understanding of how small molecules interfere with MYCN, we have now analyzed the direct binding of 10058-F4, as well as three of its analogs; #474, #764 and 10058-F4(7RH), one metabolite C-m/z 232, and a structurally unrelated c-MYC inhibitor 10074-G5, to the bHLHZip domain of MYCN. We also assessed their ability to induce apoptosis, neurite outgrowth and lipid accumulation in neuroblastoma cells. Interestingly, all c-MYC binding molecules tested also bind MYCN as assayed by surface plasmon resonance. Using a proximity ligation assay, we found reduced interaction between MYCN and MAX after treatment with all molecules except for the 10058-F4 metabolite C-m/z 232 and the non-binder 10058-F4(7RH). Importantly, 10074-G5 and 10058-F4 were the most efficient in inducing neuronal differentiation and lipid accumulation in MYCN-amplified neuroblastoma cells. Together our data demonstrate MYCN-binding properties for a selection of small molecules, and provide functional information that could be of importance for future development of targeted therapies against MYCN-amplified neuroblastoma. Topics: Amino Acid Sequence; Apoptosis; Basic-Leucine Zipper Transcription Factors; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Humans; Lipid Metabolism; Molecular Sequence Data; N-Myc Proto-Oncogene Protein; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Oxadiazoles; Protein Folding; Protein Structure, Tertiary; Proteolysis; Proto-Oncogene Proteins c-myc; Small Molecule Libraries | 2014 |
Dual inhibition of MAGL and type II topoisomerase by N-phenylmaleimides as a potential strategy to reduce neuroblastoma cell growth.
The endocannabinoid system is implicated in numerous physiopathological processes while more and more pieces of evidence wave the link between this complex machinery and cancer related phenomenon. In these lines, we confirmed the effects of 2-arachidonoylglycerol (2-AG), the main endocannabinoid, on neuroblastoma cells proliferation in vitro, and proved that some N-phenylmaleimide compounds that were previously shown as MAGL inhibitors can also inhibit type 2 topoisomerase. We also shed light on their antiproliferative effects on a neuroblastoma cell line. In order to establish a link between MAGL inhibition, topoisomerase inhibition and the effects on N1E-115 cells, we tested combinations of maleimides or known endocannabinoid metabolism inhibitors and 2-AG, the major MAGL substrate, on N1E-115 cells. However, none of the inhibitors tested, except the carbamate CAY10499, managed to increase 2-AG's effects. Even the MAGL reference inhibitor JZL184 failed to induce a stronger inhibition of proliferation. Topics: Antineoplastic Agents; Arachidonic Acids; Benzodioxoles; Cannabinoid Receptor Modulators; Carbamates; Cell Proliferation; DNA Topoisomerases, Type II; Endocannabinoids; Etoposide; Glycerides; Humans; Maleimides; Monoacylglycerol Lipases; Neuroblastoma; Oxadiazoles; Piperidines; Topoisomerase II Inhibitors; Tumor Cells, Cultured | 2012 |
Characterization of transcriptional regulation of neurogranin by nitric oxide and the role of neurogranin in SNP-induced cell death: implication of neurogranin in an increased neuronal susceptibility to oxidative stress.
Neurogranin (Ng), a calmodulin (CaM)-binding protein kinase C (PKC) substrate, regulates the availability of Ca(2+)/CaM complex and modulates the homeostasis of intracellular calcium in neurons. Previous work showed Ng oxidation by NO donor induces increase in [Ca(2+)](i). The current study demonstrated that the gene transcription of Ng could be up-regulated by various nitric oxide (NO) donors via a NO-soluble guanylyl cyclase (sGC)-mediated pathway. Furthermore, ectopic expression of neuronal nitric oxide synthase (nNOS) in human embryonic kidney 293 cells (HEK 293) exhibited a nNOS-concentration-dependent biphasic regulatory effect on Ng gene transcription. One of the NO donors, sodium nitroprusside (SNP), however, induced cell death of neuroblastoma Neuro-2a cells. The potency of SNP-induced cell death was shown to be higher in Neuro-2a cells expressing recombinant Ng, as compared with Neuro-2a control cells without Ng expression in cell viability and apoptosis assays. Single-cell fluorescence imaging and site-directed mutagenesis studies suggest that Ng promotes SNP-induced cell death through an amplification of calcium-mediated signaling, which requires the interaction between CaM and IQ motif of Ng. Increased neuronal susceptibility rendered by Ng in response to pathophysiological NO production is suggested to be involved in the selective vulnerability of neurons to oxidative insults in the CNS. Topics: Amino Acid Motifs; Animals; Apoptosis; Calcium; Calcium Signaling; Calmodulin; Cell Line; Cell Line, Tumor; Guanylate Cyclase; Homeostasis; Humans; Hypothalamus; Kidney; Mice; Mutagenesis, Site-Directed; Neuroblastoma; Neurogranin; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Nitroprusside; Oxadiazoles; Oxidative Stress; Promoter Regions, Genetic; Protein Interaction Mapping; Quinoxalines; Recombinant Fusion Proteins; Transfection | 2007 |
Different signalling pathways mediate the opposite effects of endogenous versus exogenous nitric oxide on hydroperoxide toxicity in CHP100 neuroblastoma cells.
The results presented in this study indicate that the toxic response brought about by increasing concentrations of tert-butylhydroperoxide in CHP100 cells was mitigated significantly by exogenously added nitric oxide donors via a cyclic GMP-independent mechanism. In contrast with these results, endogenous nitric oxide generated by the Ca2+-mobilizing agent caffeine was found to increase hydroperoxide toxicity. Under these conditions, nitric oxide was not directly toxic to the cells. Rather, nitric oxide was found to promote the caffeine-mediated release of Ca2+ from ryanodine-sensitive Ca2+ stores via a cyclic GMP-independent mechanism. Release of the cation from ryanodine-sensitive Ca2+ stores was causally linked with the caffeine/nitric oxide-mediated enhancement of tert-butylhydroperoxide toxicity. It is concluded that endogenous and exogenous nitric oxide activate diverging signalling pathways independent of cyclic GMP formation and causing opposite effects on the toxic response evoked by tert-butylhydroperoxide in CHP100 cells. Topics: Caffeine; Calcium; Cell Survival; Cyclic GMP; Guanylate Cyclase; Humans; Kinetics; Neuroblastoma; Nitric Oxide; Nitric Oxide Donors; Oxadiazoles; Penicillamine; Quinoxalines; S-Nitroso-N-Acetylpenicillamine; Signal Transduction; tert-Butylhydroperoxide; Tumor Cells, Cultured | 1999 |
Characterisation of the L- and N-type calcium channels in differentiated SH-SY5Y neuroblastoma cells: calcium imaging and single channel recording.
We have used single cell imaging of [Ca2+]i and single channel cell-attached patch clamp recording to characterise the Ca2+ channels present on the plasma membrane of retinoic acid-differentiated human neuroblastoma (SH-SY5Y) cells. Exposure to raised K+ (45 or 60 mM) for 1 min resulted in a transient rise in [Ca2+]i which was abolished by cadmium (100 microM). The amplitude of the evoked rise varied from cell to cell. Both omega-Conus toxin (500 nM) and nifedipine (10 microM) reduced, but did not abolish, the rise in [Ca2+]i whereas Bay K 8644 (3 microM) potentiated it. In single channel records both L- and N-type Ca2+ channel openings were observed during membrane depolarisations from a holding potential of -90 mV. L-type channel openings (unitary conductance 22.5 pS) were prolonged by S(+)-PN 202-791 (500 nM) and could still be evoked from a depolarised holding potential (-40 mV). N-type channel openings (unitary conductance 12.5 pS) were unaffected by the dihydropyridine agonist but were inactivated at a holding potential of -40 mV. These results indicate that, in contrast to previous observations using whole cell recording, retinoic acid-differentiated SH-SY5Y cells express both L- and N-type Ca2+ channels. Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Cadmium; Cadmium Chloride; Calcium; Calcium Channel Blockers; Calcium Channels; Cell Differentiation; Cell Line; Cell Membrane; Chlorides; Evoked Potentials; Fura-2; Humans; Kinetics; Microscopy, Fluorescence; Neuroblastoma; Nicotinic Acids; Nifedipine; omega-Conotoxins; Oxadiazoles; Peptides, Cyclic; Potassium; Tretinoin | 1992 |
Preferential coupling of cell surface muscarinic receptors to phosphoinositide hydrolysis in human neuroblastoma cells.
The ability of muscarinic receptors, present in either the cell surface or sequestered compartments of intact human SK-N-SH neuroblastoma cells, to stimulate phosphoinositide hydrolysis has been examined. When cells were first exposed to carbachol for 1 h at 37 degrees C, approximately 50% of the cell surface receptors became sequestered, and this was accompanied by a comparable reduction in the subsequent ability of muscarinic agonists to stimulate phosphoinositide turnover, as monitored by the release of labeled inositol phosphates at 10 degrees C. At this temperature, muscarinic receptor cycling between the two cell compartments is prevented. Upon warming the carbachol-pretreated cells to 37 degrees C, receptor cycling is reinitiated and stimulated phosphoinositide turnover is fully restored within 5-8 min. When measured at 10 degrees C, the reduction of stimulated phosphoinositide turnover observed following carbachol pretreatment was similar in magnitude for both hydrophilic (carbachol, oxotremorine-M) and lipophilic (arecoline, oxotremorine-2, and L-670,548) agonists. The loss of response for both groups of agonists could be prevented if the incubation temperature was maintained at 37 degrees C, rather than at 10 degrees C. At the latter temperature carbachol pretreatment of SK-N-SH cells reduced the maximum release of inositol phosphates elicited by either carbachol or L-670,548 but not the agonist concentrations required for half-maximal stimulation. Radioligand binding studies, carried out at 10 degrees C, indicate that following receptor sequestration, significantly higher concentrations of carbachol were required to occupy the available muscarinic receptor sites. In contrast the lipophilic full agonist L-670,548 recognized receptors present in control and carbachol-pretreated cells with comparable affinities. Analysis of the inositol lipids present after carbachol pretreatment indicate that only a minimal depletion of the substrates necessary for phospholipase C activation had occurred. The results indicate that the agonist-induced sequestration of muscarinic receptors from the cell surface results in a loss of stimulated phosphoinositide hydrolysis when measured under conditions in which the return of the sequestered receptors to the cell surface is prevented. Thus, only those receptors present at the cell surface are linked to phospholipase C activation. Topics: Bridged Bicyclo Compounds, Heterocyclic; Carbachol; Chromatography, High Pressure Liquid; Humans; Hydrolysis; Neuroblastoma; Oxadiazoles; Phosphatidylinositols; Radioligand Assay; Receptors, Cholinergic; Receptors, Muscarinic; Scopolamine; Temperature; Tumor Cells, Cultured | 1991 |
Different mechanisms of Ca2+ entry induced by depolarization and muscarinic receptor stimulation in SH-SY5Y human neuroblastoma cells.
Depolarization by elevated K+ and stimulation of muscarinic M3 receptors evoke rises in [Ca2+]i in Fura 2-loaded SH-SY5Y human neuroblastoma cells. The response to K+ (30 and 60 mM) could be inhibited by the dihydropyridine L-channel antagonist +PN 200-110 and totally suppressed by Ni2+, the N-channel blocker omega-conotoxin reduced the response to 60 mM K+. Carbachol-stimulated increase in [Ca2+]i was blocked by atropine and Ni2+ but was totally resistant to the L- and N-channel blockers. This study reveals the presence of L- and N-type voltage-sensitive Ca2+ channels on undifferentiated SH-SY5Y cells that are opened by K+ depolarization but not by muscarinic stimulation. Topics: Atropine; Calcium; Calcium Channel Blockers; Carbachol; Cell Line; Cell Membrane; Humans; Isradipine; Kinetics; Membrane Potentials; Neuroblastoma; Nickel; Oxadiazoles; Potassium; Receptors, Muscarinic | 1990 |
Calcium currents of neuroblastoma x glioma hybrid cells after cultivation with dibutyryl cyclic AMP and nickel.
The long-term modulation of calcium (Ca2+) currents (ICa) was studied in 108CC15 neuroblastoma x glioma hybrid (NxG) cells grown under various culture conditions. The following results were obtained: 1. Addition of 1 mM dibutyryl cyclic adenosine monophosphate (db-cAMP) or 0.1 microM forskolin to the culture medium increased a transient component of ICa two-fold within 3 days, from 21.0 +/- 1.6 pA/pF (n = 22) to a maximum of 40.0 +/- 2.6 pA/pF (n = 28). Under these conditions, cells also expressed a slowly inactivating ICa component (maximum after 3 days, 20.5 +/- 1.6 pA/pF, n = 28). 2. The fast inactivating ICa as well as the db-cAMP-induced slowly inactivating ICa were completely down-regulated during incubation of NxG cells with the inorganic Ca2+ channel blocker, nickel (Ni2+, 100 microM). The suppressing effect was reversed within 3 days of incubation in db-cAMP-containing medium lacking Ni2+. 3. Binding studies on membrane preparations of control and Ni2(+)-pretreated NxG cells revealed a marked difference in the maximal (+)3H-PN200-110 binding. The difference was seen in undifferentiated as well as in db-cAMP-incubated cells. 4. The protein synthesis blocker, cycloheximide, suppressed both the db-cAMP-induced increase and the reappearance of ICa following Ni2+ pretreatment. It is suggested that chronic application of db-cAMP or Ni2+ to NxG cells increases and decreases the number of Ca2+ channel proteins, respectively. Topics: Animals; Bucladesine; Calcium Channels; Colforsin; Cycloheximide; Glioma; Hybrid Cells; Isradipine; Mice; Neuroblastoma; Nickel; Oxadiazoles; Rats; Tumor Cells, Cultured | 1990 |
L-glutamate binding site on N18-RE-105 neuroblastoma hybrid cells is not coupled to an ion channel.
We studied the properties of the N18-RE-105 neuronal cell line to determine if its glutamate binding site represents a neurotransmitter receptor. In immunocytochemical experiments, these cells stained strongly for neurofilament, but not for glial fibrillary acidic protein. In whole-cell patch clamp experiments, cells exhibited voltage-dependent Na+, Ca2+, and K+ currents characteristic of neurons. However, perfusion with L-glutamate or other excitatory amino acids did not evoke the inward current expected of a receptor/channel complex. In binding studies, the maximum accumulation of L-[3H]glutamate by washed membrane vesicles at 37 degrees C was 69 pmol/mg protein, and half-maximal accumulation occurred at 0.64 microM. This accumulation was blocked completely by quisqualate, partially by DL-2-amino-4-phosphonobutyric acid and L-cystine, but not at all by 1 mM kainate or N-methylaspartate. L-[3H]Glutamate accumulation was stimulated by Cl-, but reduced by Na+, 0.01% digitonin, or hyperosmotic (400 mM glucose) assay medium. The release of L-[3H]glutamate from vesicles was much faster in the presence of 100 microM unlabelled glutamate than 100 microM unlabelled quisqualate or DL-2-amino-4-phosphonobutyric acid. Thus, although N18-RE-105 cells possess many neuronal properties, the results obtained are not those expected from reversible binding of L-glutamate to a receptor/channel complex, but are consistent with a Cl- -stimulated sequestration or exchange process. Topics: Aminobutyrates; Animals; Binding, Competitive; Calcium; Chlorides; Cystine; Electric Conductivity; Fluorescent Antibody Technique; Glutamates; Glutamic Acid; Hybrid Cells; Intermediate Filament Proteins; Ion Channels; Mice; Neuroblastoma; Neurofilament Proteins; Neurons; Oxadiazoles; Potassium; Quisqualic Acid; Rats; Receptors, Glutamate; Receptors, Neurotransmitter; Sodium; Tumor Cells, Cultured | 1988 |
Glutamate cytotoxicity in a neuronal cell line is blocked by membrane depolarization.
To understand better the proximate mechanism involved in the excitotoxic response to L-glutamate (Glu), we have exploited the Glu receptor present in the N18-RE-105 neuroblastoma-embryonic retinal hybrid cell line. These cells undergo lysis dependent on extracellular Ca2+ when exposed to Glu. We now report that the depolarizing action of Glu is not responsible for its cytotoxic effects. Furthermore, depolarization of these cells with elevated K+, ouabain or veratridine does not cause cytotoxicity but rather protects against the cytotoxic effects of Glu. Our results may implicate a role for voltage-sensitive Ca2+ channels (VSCCs) in cytotoxicity, and depolarization-induced inactivation of VSCCs (Nature (Lond.), 316 (1985) 440-443) as a protection against Glu receptor agonists. Our findings demonstrate a clear dissociation between depolarization and the neuronal degeneration caused by Glu. Topics: Animals; Cell Line; Glutamates; Glutamic Acid; Hybrid Cells; Ibotenic Acid; Membrane Potentials; Neuroblastoma; Neurons; Neurotoxins; Oxadiazoles; Quisqualic Acid; Retina | 1988 |