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)

The noncompetitive S-adenosylhomocysteine (AdoHcy) hydrolase antagonist adenosine dialdehyde (AD) has been shown to suppress the growth of cultured C-1300 murine neuroblastoma (MNB) cells. The enzymatic sites at which AD and other nucleoside analogues exert their cytotoxic effects have been postulated to include protein carboxylmethyltransferase (PCM), AdoHcy hydrolase, and ribonucleotide reductase. AD (10(-5) M) increased PCM activity 350% in suspensions prepared from disrupted cells after 72 h of drug exposure; in contrast, 3-deazaadenosine (10(-4) M) increased PCM activity 57%, whereas AdoHcy and sinefungin had no effect. When intact MNB cells were incubated with AD for varying time periods up to 72 h and then pulse labeled with the S-adenosylmethionine precursor L-[3H]-methionine, AD (10(-8) to 5 X 10(-6) M) produced a concentration-dependent inhibition of protein carboxylmethylation which persisted for up to 6 h. Following extended periods of AD treatment (48 to 72 h), AD (10(-6) to 10(-5) M) produced a 250% increment in protein carboxylmethylation, similar in magnitude to that observed in disrupted cell preparations. This increase in carboxylmethylation was observed at timepoints when AdoHcy hydrolase activity remained suppressed. The inhibitory effect of AD on AdoHcy hydrolase activity was maximal within 4 h and still apparent after 72 h of incubation. In contrast, AD treatment had no effect on the ribonucleotide reductase activity of MNB cells. These data suggest that the cytotoxic effect of AD on MNB cells results directly from its inhibition of AdoHcy hydrolase activity and indirectly through its suppression of methyltransferase enzyme systems. The potential linkage between the observed long-term elevations in PCM activity and AD-induced cytotoxicity remains to be defined.
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PMID:Effect of adenosine analogues on protein carboxylmethyltransferase, S-adenosylhomocysteine hydrolase, and ribonucleotide reductase activity in murine neuroblastoma cells. 329 6

Early passage cultures of neuroblastoma cells were tested for (i) cellular sensitivity to the methylating agent 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC); (ii) ability to reactivate MTIC-damaged adenovirus (Mer+ phenotype); and (iii) methyltransferase activity. Seven of eight lines were resistant to MTIC. One line had an intermediate level of cellular resistance to MTIC, when compared with Mer+ and Mer- control lines. Methyltransferase activity of the neuroblastomas was intermediate between Mer+ and Mer- control. Unlike other methylation-resistant cell types, the neuroblastomas showed an initial decline in the MTIC dose-response profile for cell survival followed by a plateau at higher doses. In the virus reactivation assay (HCR), the slope (D0) of the virus survival curve at high MTIC doses for cells from three of 10 patients was similar to that of Mer- controls. The D0 for the remaining seven was also much less than for Mer+ controls. However, due to shoulders on the survival curves, all of the neuroblastomas could be classified as Mer+ at low levels of MTIC damage. Overall, the neuroblastoma cells appeared to form a new, though heterogeneous, methylation-resistant group, with cell survival not paralleled by methyltransferase activity or virus reactivation at high methylation levels.
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PMID:Sensitivity of human neuroblastoma to activated dacarbazine: relationships between cell survival, methyltransferase activity and activation of adenovirus-5. 340 48

Guanidinoacetate methyltransferase, the enzyme catalyzing the last step in creatine biosynthesis, has previously been considered to be restricted to a few tissues, but it has been found to occur in the cultured cells H4Az C2 rat hepatoma, N4TG1 mouse neuroblastoma, and IMR-90 human fetal lung fibroblast, as well as in skeletal and cardiac muscle of the rat. Activity was highest in the hepatoma, but tissues and cultured cells of nonhepatic origin had 5-20% of the activity of rat liver. Dialyzed 100,000g supernatants prepared from cultured cells or skeletal muscle tissue yielded values for apparent Km in the range of 1.2-3.4 microM for S-adenosylmethionine and 0.050-0.096 mM for guanidinoacetate. Intact monolayers of the three types of cultured cells converted labeled guanidinoacetate in the culture medium to creatine, which was identified by chromatographic behavior and by reaction with creatine kinase. The amounts of guanidinoacetate converted to creatine by fibroblasts and neuroblastoma cells during an 18-h period of incubation suggested that synthesis was proceeding at rates approaching Vmax, even in medium containing the relatively low physiological concentrations of guanidinoacetate. Fibroblast and neuroblastoma cell monolayers also have the capacity to take up creatine provided in the culture medium. The amounts of creatine taken up by monolayers of those cells were measured under the same conditions that were used for measurement of creatine synthesis. Comparison of the amounts of creatine synthesized with the amounts taken up showed that synthesis can make a significant contribution to intracellular pools of creatine plus phosphocreatine in fibroblasts and neuroblastoma cells.
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PMID:Guanidinoacetate methyltransferase activity in tissues and cultured cells. 397 May 26

Protein carboxy-O-methyltransferase (PCM) activity was determined in subcellular fractions prepared from C-1300 neuroblastoma tumors following transplantation and growth in male A/J mice. Fractions were obtained by differential centrifugation, and PCM activity was determined in all fractions in the presence (+gel) and absence (-gel) of an exogenous substrate, gelatin. Sixty % of the PCM activity in the absence of exogenous substrate (-gel) was contained in the crude 800 X g particulate fraction, whereas 80% of the PCM activity in the presence of gelatin (+gel) was present in the postmicrosomal (100,000 X g) supernatant. The latter fraction also contained the highest specific activity of PCM. A Km of 3.2 X 10(-6) M and a Vmax of 5.3 pmol per mg protein per min were obtained for PCM activity (+gel) in the high-speed supernatant. Cytoplasmic PCM was highly sensitive to competitive inhibition by S-adenosylhomocysteine and the S-adenosyl-homocysteine analogs sinefungin and A-9145C with Ki values of 0.64, 0.47, and 0.05 microM, respectively. These data demonstrate that PCM present in murine neuroblastoma has characteristics similar to those of PCM isolated from other adrenergic and neuronal tissues. S-Adenosyl-homocysteine analogs may be useful probes for studying the role of PCM as a modulator of cell function in neurogenic and neoplastic tissues.
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PMID:Characterization of protein carboxyl-O-methyltransferase in the spontaneous in vivo murine C-1300 neuroblastoma. 712 84

An endogenous neurotoxin, N-methyl(R)salsolinol, has been proved to be involved in the pathogenesis of Parkinson's disease. Increased level of N-methyl(R)salsolinol in the cerebrospinal fluid and high activity of its synthesizing (R)salsolinol N-methyltransferase in lymphocytes were confirmed in the majority of parkinsonian patients. Recently this neurotoxin was found to induce apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells. In this study, we tried to elucidate the intracellular mechanism of apoptosis induced by N-methyl(R)salsolinol, and proved activation of caspase 3 after incubation with this toxin by Western blot analysis. Further, a caspase 3 inhibitor, acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartic aldehyde, prevented the nucleosomal DNA fragmentation completely. These results demonstrate that caspase 3 mediates apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, which may cause apoptotic cell death of dopamine neurons in Parkinson's disease.
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PMID:Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, is mediated by activation of caspase 3. 1038 Sep 99

A dopamine-derived neurotoxin, 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2, 3,4-tetrahydroisoquinoline [N-methyl(R)salsolinol] was found to cause parkinsonian in rats and to deplete selectively dopamine neurons in the substantia nigra after infusion in the striatum. This isoquinoline occurs enantio-specifically in the nigra-striatum of human brains. The biosynthesis from dopamine is catalyzed by two enzymes, (R)salsolinol synthase and (R)salsolinol N-methyltransferase. The isoquinoline increases in the cerebrospinal fluid from parkinsonian patients, and the increase is ascribed to high activity of its synthesizing neutral (R)salsolinol N-methyltransferase, as shown by analyses in lymphocytes. The cell death caused by this neurotoxin in dopaminergic human neuroblastoma SH-SY5Y cells proved to be apoptotic. Apoptosis by this neurotoxin is mediated by intracellular sequential process, loss of mitochondrial membrane potential, activation of caspases and DNA fragmentation. These results are discussed in relation to the role of apoptosis in neurodegenerative diseases and the involvement of the endogenous toxin in the pathogenesis of Parkinson's disease.
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PMID:Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopamine neurons. 1109 Sep 52

An endogenous dopamine-derived N-methyl(R)salsolinol has been suggested to be involved in the pathogenesis of Parkinson's disease. In Parkinson's disease, the level of N-methyl(R)salsolinol increased in cerebrospinal fluid and the high activity of a synthesizing enzyme, (R)salsolinol N-methyltransferase, was detected in lymphocytes. This isoquinoline induced apoptotic DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. Among catechol isoquinolines, only N-methylsalsolinol induced apoptosis in the cells, and the scavengers of hydroxyl radicals and antioxidants suppressed DNA damage, suggesting that reactive oxygen species initiate apoptosis. The isoquinoline activated caspase-3 like proteases and a caspase-3 inhibitor protected the cells from DNA damage. (-)Deprenyl, but neither clorgyline nor pargyline, prevented apoptotic cell death. The mechanism of the protection was due to stabilization of mitochondrial membrane potential reduced by the toxin. In Parkinson's disease apoptosis may be induced in dopamine neurons by this endogenous neurotoxin, and (-)deprenyl may protect them from apoptotic death process.
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PMID:Involvement of endogenous N-methyl(R)salsolinol in Parkinson's disease: induction of apoptosis and protection by (-)deprenyl. 1112 1

We have previously reported that C-1300 murine neuroblastoma (rMNB) cells made resistant to the nucleoside analogue, (Z)-5'-fluoro-4', 5'-didehydro-5'deoxyadenosine (MDL), an irreversible inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase have an increased expression of the S-adenosylmethionine (AdoMet) synthetase gene. Results of the immunoblot analysis of DNA (cytosine) methyltransferase with anti-human DNA (cytosine) methyltransferase specific polyclonal antibody demonstrated a significant increase ( approximately 2-fold, p<0.01) in expression of DNA (cytosine) methyltransferase protein in rMNB/MDL cells compared to wild-type C1300 MNB (wMNB) cells. To rule out the possibility that multidrug resistance (MDR) genes are involved in development of acquired drug resistance in murine neuroblastoma (rMNB/MDL) cells made resistant to MDL, the expression of Mdr1a, Mdr1b, Mdr2 (multidrug resistance/P-glycoprotein), and Mrp-1 (multidrug resistance associated protein) was examined in rMNB-MDL cells. The analysis of Mdr and Mrp-1 expression was performed by RT-PCR using PCR specific primers to respective genes. No significant difference was observed in the expression of MDR1a, Mdr1b and Mrp-1 genes between wMNB and rMNB-MDL cells, however, a slight decrease was noticed in Mdr1 expression in some samples. Expression of the Mdr2 (human MDR3) gene, which is not associated with the acquired drug resistance phenotype, was significantly decreased in rMNB-MDL cells. These findings were also confirmed by the immunoblot analyses using specific monoclonal antibodies to Mdr1/3 proteins. Expression of N-Myc gene--a prognostic factor in neuroblastoma tumors was also not altered in rMNB-MDL cells. Results of the present study suggest that acquired drug resistance in rMNB-MDL cells to MDL is associated to the overexpression of DNA (cytosine) methyltransferase, and could be due to genetic or epigenetic changes in particular to DNA hypermethylation in response to an increased AdoMet synthetase gene expression.
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PMID:DNA (cytosine) methyltransferase overexpression is associated with acquired drug resistance of murine neuroblastoma cells. 1117 99

The etiology of idiopathic Parkinson's disease remains as an enigma. N-Methyl (R)salsolinol [NM (R) Sal] is a candidate of dopaminergic neurotoxins, and is synthesized from dopamine by 2 enzymes: (R) Salsolinol synthase and a neutral (R) Salsolinol N-methyltransferase (nNMT). NM (R) Sal injection in the rat striatum caused selective depletion of dopamine neurons in the substantia nigra without tissue reaction, suggesting NM (R) Sal induced apoptosis in dopamine neurons. NM (R) Sal level was found to increase significantly in the cerebrospinal fluid of parkinsonian patients, and NM (R) Sal accumulated in the nigrostriatum. By the analysis of the human brain, it was suggested nNMT is the rate-limiting step to synthesize dopamine-derived neurotoxins. The activity of nNMT was found to increase in the lymphocytes from parkinsonian patients. The mechanism of toxicity by NM (R) Sal was studied in vitro using human dopaminergic neuroblastoma SH-SY5Y cells. NM (R) Sal induced apoptosis stereo-specifically, suggesting that a molecule in mitochondria can distinguish the stereo-chemical structure of NM (R) Sal and activate intracellular signal of apoptosis. Recently, we found that propargylamines, inhibitors of type B monoamine oxidase, can prevent the apoptosis induced by NM (R) Sal. Further study on the mechanism underlying increase in nNMT activity in parkinsonian patients will clarify the involvement of genetic and environmental factors in the pathogenesis of Parkinson's disease.
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PMID:[Studies on endogenous toxins as pathogenic factors in idiopathic parkinson's disease]. 1118 1

The cause of neuronal cell death in Parkinson's disease is still an enigma. However, recent results obtained by analyses of postmortem brain suggest that a mitochondria-dependent apoptotic signal was activated. The involvement of dopamine-derived endogenous neurotoxin in the pathogenesis of PD was also indicated. N-Methyl( R)salsolinol was proved to be selectively toxic to dopamine neurons and its level increased in parkinsonian CSF. The enzyme which determines the level of N-methyl( R)salsolinol, ( R)salsolinol N-methyltransferase, was found increased in the lymphocytes prepared from PD patients. The mechanism of dopamine cell death by N-methyl( R)salsolinol was studied in vitro. N-Methyl( R)salsolinol induced apoptosis in human dopaminergic neuroblastoma cells. It was suggested that in the mitochondria there is a molecule which interacts with N-methyl( R)salsolinol and initiates an apoptotic signal.
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PMID:Cell death in Parkinson's disease. 1237 57


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