Resistance to inhibitors of S-adenosyl-L-homocysteine hydrolase in C1300 murine neuroblastoma tumor cells is associated with increased methionine adenosyltransferase activity.
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.
Hamre
M R
MR
Department of Pediatrics, Northwestern University, Chicago, IL 60614, USA.
Clark
S H
SH
Mirkin
B L
BL
D000241:Adenosine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D008297:Male; D008716:Methionine Adenosyltransferase / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014316:Tritium; C065189:4',5'-didehydro-5'-deoxy-5'-fluoroadenosine; C048460:3-deazaneplanocin; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008716:Methionine Adenosyltransferase; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine