Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Neuronal apoptotic execution uses a cytochrome c-dependent caspase activation mechanism that is conserved in other cell types. Phosphatidylinositol 3-kinase and its downstream effector, Akt/protein kinase B, appear to control this mechanism and govern the life/death decision. We have developed a cell-free system using cytosol from human neuroblastoma (SY5Y) cells that reconstitutes biochemical features of neuronal apoptosis. In the presence of cytochrome c and ATP, caspase-9 and -3 were activated, which initiated chromatin condensation and DNA cleavage in rat pheochromocytoma (PC12) nuclei. Akt was cleaved in reactions where caspase-3 was activated and its cleavage was prevented by the caspase inhibitor DEVD-aldehyde. The phosphatase inhibitors orthovanadate and okadaic acid prevented catalytic processing and activation of caspase-3 and digestion of Akt and partially inhibited cleavage of caspase-9. Caspase-dependent destruction of Akt irreversibly inactivates this key mediator of survival signaling, ensuring that the execution pathway will prevail.
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PMID:Phosphorylation-dependent Akt cleavage in neural cell in vitro reconstitution of apoptosis. 1050 Dec 28

Photoaffinity analogues of alpha-tocopherol have been prepared by substituting photosensitive functional groups at either the terminus of an alkyl chain of varying length mimicking the phytyl tail or on C-3 of the chroman portion of tocopherol. The alkyl chain-modified compounds 2a-d contain a hexyl to nonyl alkyl chain extending from C-2 of the chroman, terminating in a tetrafluoroazidobenzyloxy group. These compounds were prepared starting from the commercially available Trolox acid 4, followed by esterification, protection, and reduction to the silyl-protected Trolox aldehyde 7, which was coupled using Wittig chemistry to different omega-hydroxyphosphonium bromides. Reduction of the alkene product, coupling with p-azidotetrafluorobenzyl bromide, and deprotection of the phenolic silyl group gave compounds 2a-d in excellent yields. Chroman-functionalized photoaffinity labels were synthesized starting from the protected tocopherol chromene 16b which was a key intermediate for preparation of a 3-hydroxy derivative, either by reduction of epoxides produced directly with Jacobsen's catalysts or by treatment with NBS in wet DME to give two stereoisomeric bromohydrins which were cyclized and reduced to give the phenol-protected C-3 alcohols 19a,b. These alcohols were then converted to diazoacetate esters, and the protecting group was removed to give 3-diazoacetoxy alpha-tocopherols 3a,b.
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PMID:Synthesis of phytyl- and chroman-derivatized photoaffinity labels based on alpha-tocopherol. 1078 72

Ring-closing metathesis has been applied to a series of glucose derivatives to produce cyclopentene derivatives 5a and 5b, cyclohexene derivatives 8 and 9, cycloheptene 12, and cyclooctene 14. Spirocyclic dihydrofurans 19, 26a, and 26b, along with dihydropyran 22, were also produced. A range of fused oxepine derivatives 29a-c and one oxo-cyclononene 31 were also prepared. Cyclopentene 5b was subjected to a sequence of hydrogenation, NBS bromination, and treatment with powdered zinc to furnish the ring-expanded product 35. No such ring expansion occurred when the cyclohexaannulated compound 8 was treated with NBS followed by powdered zinc, leading to aldehyde 39. The spiro dihydrofuran derivative 19 was converted to the aldehyde 42 via the same reaction sequence used to fragment cyclopentene derivative 5b.
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PMID:Stereoselective preparation of enantiomerically pure annulated carbohydrates using ring-closing metathesis 1081 61

Apoptosis of NG108-15 neuroblastoma x glioma hybrid cells (NG108-15 cells) is induced by a morphine alkaloid derivative, buprenorphine hydrochloride (Bph). In a previous report, we used various apoptosis inhibitors to identify the "death pathway," and found that caspase inhibitors Ac-YVAD-CHO (Ac-Tyr-Val-Ala-Asp-CHO) and Ac-DEVD-CHO (Ac-Asp-Glu-Val-Asp-CHO) did not inhibit this particular apoptosis. Here, we tested Z-VAD-FMK (Z-Val-Ala-Asp[OMe]-CH2F) and Z-DEVD-FMK (Z-Asp[OMe]-Glu-[OMe]Val-Asp[OMe]-CH2F) for their ability to inhibit Bph-induced NG108-15 apoptosis. These tri- or tetra-peptide caspase inhibitors have a fluoromethyl ketone in their C-terminus instead of an aldehyde, and thus are more permeable than Ac-YVAD-CHO and AC-DEVD-CHO. Our observations of DNA ladder formation, cell morphology changes, and caspase-3 activities all indicated that these cell membrane-permeable caspase inhibitors completely inhibited the apoptosis, providing strong evidence that this apoptosis occurs through the caspase cascade "death pathway." Our previous report also showed that pretreatment of NG108-15 cells with TPCK (N-tosyl-L-phenylalanyl chloromethyl ketone) prevented DNA fragmentation and decreased the cell viability in Bph-induced apoptosis. The comparison of caspase-3 activities in Bph-induced samples with or without TPCK pretreatment revealed that caspase-3 was activated in both samples. Taken together, these results indicate that the Bph-induced apoptosis of NG108-15 cells occurs via the conventional caspase-dependent death pathway and that TPCK pretreatment results in a DNA ladder-deficient apoptosis.
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PMID:Apoptosis of NG108-15 cells induced by buprenorphine hydrochloride occurs via the caspase-3 pathway. 1096 98

Neuroblastoma is the most common extracranial solid tumor of childhood. N-type neuroblastoma cells (represented by SH-SY5Y and IMR32 cell lines) are characterized by a neuronal phenotype. N-type cell lines are generally N-myc amplified, express the anti-apoptotic protein Bcl-2, and do not express caspase-8. The present study was designed to determine the mechanism by which N-type cells die in response to specific cytotoxic agents (such as cisplatin and doxorubicin) commonly used to treat this disease. We found that N-type cells were equally sensitive to cisplatin and doxorubicin. Yet death induced by cisplatin was inhibited by the nonselective caspase inhibitor z-Val-Ala-Asp-fluoromethylketone or the specific caspase-9 inhibitor N-acetyl-Leu-Glu-His-Asp-aldehyde, whereas in contrast, caspase inhibition did not prevent doxorubicin-induced death. Neither the reactive oxygen species nor the mitochondrial permeability transition appears to play an important role in this process. Doxorubicin induced NF-kappa B transcriptional activation in association with I-kappa B alpha degradation prior to loss of cell viability. Surprisingly, the antioxidant and NF-kappa B inhibitor pyrrolidine dithiocarbamate blocked doxorubicin-induced NF-kappa B transcriptional activation and provided profound protection against doxorubicin killing. Moreover, SH-SY5Y cells expressing a super-repressor form of I-kappa B were completely resistant to doxorubicin killing. Together these findings show that NF-kappa B activation mediates doxorubicin-induced cell death without evidence of caspase function and suggest that cisplatin and doxorubicin engage different death pathways to kill neuroblastoma cells.
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PMID:NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. 1167 90

A new method for obtaining optically pure 5-norbornene 2-endo-aldehyde derivatives was developed. The reaction of a diastereomeric mixture of the ene acetals 2 and 2', derived from racemic norbornene aldehydes (+/-)-1 and chiral nonracemic (S,S)-hydrobenzoin 7, with NBS (0.5-0.6 eq.) in the presence of H(2)O proceeded in a kinetically controlled manner to give the optically pure hydroxy aldehydes 3 along with the intact ene acetals 2'. Both compounds 3 and 2' were converted into the optically pure norbornene aldehydes 1 and ent-1, respectively. This method opens the way to produce various types of 5-norbornene 2-endo-aldehydes with 3-exo- or 3-endo-substituents in optically pure forms.
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PMID:Kinetically controlled optical resolution of racemic norbornene aldehyde derivatives. 1246 44

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is formed by the oxidative deamination of dopamine (DA) catalyzed by monoamine oxidases (MAO); then, the aldehyde is oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenases (ALDH) or reduced to 3,4-dihydroxyphenylethanol (DOPET) by aldose/aldehyde reductases. The present work aimed at evaluating the in vitro toxicity of DOPAL on catecholaminergic neuroblastoma SH-SY5Y cells which accumulate DA. DOPAL synthesis was stimulated by incubating cells with DA and blocking DOPAL oxidation by disulfiram, an irreversible inhibitor of ALDH. As evidenced by MTT reduction assays, DA and disulfiram treatments produced cell losses which increased with time. 10(-2)M DA reduced by 40% cell viability after a 1h treatment, when its TC(50) (concentration reducing viability by 50%) value was 7.3 x 10(-5) M after a 24 h treatment. For the same treatment periods, TC(50) values for disulfiram were 8 x 10(-5) and 8.7 x 10 (-7) M, respectively. MTT reduction assay performed after a 24h treatment followed by a 24h incubation in a drug-free medium evidenced that the toxicity of 10(-4)M DA or 10(-6)M disulfiram was potentiated by the second drug. HPLC measurements showed that DOPAL was produced at the early stages of the treatment by DA and disulfiram. This was evidenced by the significant increase in the ((DOPAL + DOPET)/DOPAC ratio observed after a combined 3h treatment by 10(-4)M DA and 10(-6)M disulfiram. Total contents in DA and DOPAL were greatly reduced at the end of a 15 h treatment, and disulfiram did not significantly enhanced the (DOPAL + DOPET)/DOPAC ratio. For both treatment durations, DOPAL and DOPET were detectable only in the extracellular medium. So, these results suggest that an early production of DOPAL could produce delayed toxic effects on SH-SY5Y cells. Production of DOPET and release of DOPAL could be important means for reducing DOPAL concentrations in dopaminergic neurons.
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PMID:Toxicity of a treatment associating dopamine and disulfiram for catecholaminergic neuroblastoma SH-SY5Y cells: relationships with 3,4-dihydroxyphenylacetaldehyde formation. 1501 99

3-Aminopropanal (3-AP), a degradation product of polyamines such as spermine, spermidine and putrescine, is a lysosomotropic small aldehyde that causes apoptosis or necrosis of most cells in culture, apparently by inducing moderate or extensive lysosomal rupture, respectively, and secondary mitochondrial changes. Here, using the human neuroblastoma SH-SY5Y cell line, we found simultaneous occurrence of apoptotic and necrotic cell death when cultures were exposed to 3-AP in concentrations that usually are either nontoxic, or only cause apoptosis. At 30 mM, but not at 10 mM, the lysosomotropic base and proton acceptor NH3 completely blocked the toxic effect of 3-AP, proving that 3-AP is lysosomotropic and suggesting that the lysosomal membrane proton pump of neuroblastoma cells is highly effective, creating a lower than normal lysosomal pH and, thus, extensive intralysosomal accumulation of lysosomotropic drugs. A wave of internal oxidative stress, secondary to changes in mitochondrial membrane potential, followed and gave rise to further lysosomal rupture. The preincubation of cells for 24 h with a chain-breaking free radical-scavenger, alpha-tocopherol, before exposure to 3-AP, significantly delayed both the wave of oxidative stress and the secondary lysosomal rupture, while it did not interfere with the early 3-AP-mediated phase of lysosomal break. Obviously, the reported oxidative stress and apoptosis/necrosis are consequences of lysosomal rupture with ensuing release of lysosomal enzymes resulting in direct/indirect effects on mitochondrial permeability, membrane potential, and electron transport. The induced oxidative stress seems to act as an amplifying loop causing further lysosomal break that can be partially prevented by alpha-tocopherol. Perhaps secondary brain damage during a critical post injury period can be prevented by the use of drugs that temporarily raise lysosomal pH, inactivate intralysosomal 3-AP, or stabilize lysosomal membranes against oxidative stress.
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PMID:Human neuroblastoma (SH-SY5Y) cells are highly sensitive to the lysosomotropic aldehyde 3-aminopropanal. 1524 52

A novel asymmetric synthesis of the cyclohexane derivative functionalized by some substituents has been developed from the diene acetals (1), prepared from the corresponding diene aldehyde and (+)-hydrobenzoin. The treatment of 1 with NBS in the presence of MeOCH2CH2OH predominantly afforded 2 in a stereoselective manner. Subsequent alkylation of the methoxyethoxy group produced the optically active cyclohexene compounds (3) in good yields. The stereoselective chemical modification of the remaining olefin in 3 was made by OsO4-oxidation.
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PMID:Asymmetric synthesis by the intramolecular haloetherification reaction of ene acetal: discrimination of prochiral dienes in cyclohexane systems. 1607 27

The synthesis, scavenging activity, and cytoprotective profiles of histidyl-containing carnosine analogues bearing hydrazide or 1,2-diol moieties is reported. Some compounds have demonstrated higher aldehyde-sequestering efficiency than carnosine and were also efficient in protecting SH-SY5Y neuroblastoma cells and rat hippocampal neurons from 4-hydroxy-trans-2,3-nonenal (HNE)-mediated death. The cytoprotective efficacy of these compounds suggests their potential use as therapeutic agents for disorders that involve excessive membrane lipids peroxidation and HNE-mediated neuronal toxicity.
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PMID:Synthesis and evaluation of neuroprotective alpha,beta-unsaturated aldehyde scavenger histidyl-containing analogues of carnosine. 1616 15


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