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)

Adaptive changes occurring in C1300 murine neuroblastoma cell lines developed for resistance to nucleoside analogue inhibitors of S-adenosyl-L-homocysteine hydrolase (AdoHcyase, EC 3.3.1.1) were investigated. Two drug-resistant cell lines, rMNB-MDL-7-2 and rMNB-Deaz-7-2, were established from wild-type C1300 neuroblastoma cells (wMNB) following incubation with the AdoHcyase inhibitors (Z)-4',5'-didehydro-5'-deoxy-5'-fluoroadenosine (MDL 28,842) and 3-deazaneplanocin A, respectively. The nucleoside analogue concentration required to inhibit cellular proliferation by 50% (IC50) was 3.2 x 10(2) to 4.3 x 10(3) fold higher in the resistant cells when compared with the wMNB cell line. The proliferation rates of the resistant cell lines under in vitro or in vivo conditions were significantly lower than the wMNB cell line. In contrast to wMNB, both resistant cell lines had slower doubling times in tissue culture (22% longer) and smaller tumor weights (55% smaller) 14 days after implantation in A/J mice. No significant differences in AdoHcyase activity were noted between the resistant and wild-type cell lines. The resistant cell lines had concentrations of S-adenosyl-L-methionine that were five times higher and methionine adenosyltransferase (MAT, EC 2.5.1.6) activities that were two to four times greater than the wMNB phenotype. These data indicate that neuroblastoma tumor cell resistance to AdoHcyase inhibitors is associated with an adaptive increase in MAT activity. This cellular response facilitates methylation by elevating intracellular concentrations of the methyl donor S-adenosyl-L-methionine, thereby sustaining tumor cell viability in the presence of MDL 28,842 and 3-deazaneplanocin A.
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PMID:Resistance to inhibitors of S-adenosyl-L-homocysteine hydrolase in C1300 murine neuroblastoma tumor cells is associated with increased methionine adenosyltransferase activity. 886 60

The human neuroblastoma cell line SH-SY5Y was used to study the regulation of methionine adenosyltransferase (MAT II; E.C.2.5.1.6.) catalytic activity and transcript levels in cells of neuronal origin. The cells were exposed for 24 hr to a medium containing different concentrations of methionine (MAT substrate) as well as medium deficient of methionine. Furthermore, cells were treated with hydroxycobalamin, SAM, and the competitive MAT inhibitor cycloleucine. The MAT catalytic activity was inversely correlated to methionine concentrations, e.g. MAT Vmax increased 2-fold in cells grown in methionine-deficient medium as compared with cells cultured under standard conditions. Interestingly, MAT Km also increased from 9.04 +/- 0.44 to 12.08 +/- 0.83 in the methionine-deficient medium. Hydroxycobalamin caused an increase in activity at 40 microM while a decrease was observed at higher concentrations (100, 200, and 400 microM). Cycloleucine caused a significant inhibition of MAT catalytic activity, i.e. the inhibition was approximately 50% in the presence of 4 mM cycloleucine. The relevance of these results for the understanding of observations on MAT catalytic activity in brains of patients with Alzheimer's disease is discussed.
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PMID:Regulation of methionine adenosyltransferase catalytic activity and messenger RNA in SH-SY5Y human neuroblastoma cells. 951 67

S-Adenosylmethionine (AdoMet) synthetase (EC 2.5.1.6), which catalyzes the synthesis of AdoMet from methionine and ATP, is the major methyl donor for transmethylation reactions and propylamino donor for the biosynthesis of polyamines in biological systems. We have reported previously that wild-type C-1300 murine neuroblastoma (wMNB) cells, made resistant to the nucleoside analogue (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), an irreversible inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1), express increased AdoMet synthetase activity (M. R. Hamre et al., Oncol. Res., 7: 487-492, 1995). In the present study, immunoblot analyses of AdoMet Synthetase with isoform-specific (MATII) antibodies demonstrated an elevation in the AdoMet synthetase immunoprotein in nucleoside analogue-resistant MNB cells (rMNB-MDL) when compared to wild-type, nonresistant MNB cells. An increase of 2.1-fold was observed in the alpha2/alpha2' catalytic subunit, which differed significantly from the much smaller increment in the noncatalytic beta-subunit of AdoMet synthetase. Densitometric analyses revealed that an increased expression of AdoMet synthetase in rMNB-MDL cells was due to overexpression of the alpha2 (Mr 53,000; 2.6-fold) and alpha2' (Mr 51,000; 1.8-fold) subunits. AdoMet synthetase mRNA expression in rMNB-MDL cells was remarkably greater than wMNB cells, as determined by quantitative competitive reverse transcription-PCR (QC-PCR) analysis. DNA (cytosine) methyl transferase expression, measured by reverse transcription-PCR analysis, was also elevated significantly in rMNB-MDL cells. In contrast, Western blot analyses demonstrated down-regulation (1.6-fold) of AdoMet synthetase in doxorubicin-resistant human leukemia cells (HL-60-R) expressing multidrug resistance protein when compared with wild-type, nonresistant HL-60 cells. The resistance of rMNB-MDL cells to nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase correlates directly with overexpression of the alpha2/alpha2' subunits of AdoMet synthetase. Cellular adaptation allows sufficient AdoMet to be synthesized, so that viability of the MNB cells can be maintained even in the presence of high AdoHcy concentrations. This novel mechanism of drug resistance does not appear to require multidrug resistance protein (P-glycoprotein) overexpression.
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PMID:S-adenosylmethionine synthetase is overexpressed in murine neuroblastoma cells resistant to nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase: a novel mechanism of drug resistance. 1021 91

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