Inhibition of nucleoside transport by p38 MAPK inhibitors.
While investigating the ability of p38 MAPK to regulate cytarabine (Ara C)-dependent differentiation of erythroleukemia K562 cells, we observed effects that indicated that the imidazoline class of p38 MAPK inhibitors prevented nucleoside transport. Incubation of K562 cells with SB203580, SB203580-iodo, or SB202474, an analogue of SB203580 that does not inhibit p38 MAPK activity, inhibited the uptake of [3H]Ara C or [3H]uridine and the differentiation of K562 cells. Consistent with the effects of these compounds on the nitrobenzylthioinosine (NBMPR)-sensitive equilibrative nucleoside transporter (ENT1), incubation with SB203580 or SB203580-iodo eliminated the binding of [3H]NBMPR to K562 cells or membranes isolated from human erythrocytes. Furthermore, using a uridine-dependent cell type (G9c), we observed that SB203580 or SB203580-iodo efficiently inhibited the salvage synthesis of pyrimidine nucleotides in vivo. Thus these studies demonstrate that the NBMPR-sensitive equilibrative nucleoside transporters are novel and unexpected targets for the p38 MAPK inhibitors at concentrations typically used to inhibit protein kinases.
Huang
Min
M
Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Wang
Yanhong
Y
Collins
Matthew
M
Gu
Jing Jin
JJ
Mitchell
Beverly S
BS
Graves
Lee M
LM
D051777:AraC Transcription Factor; D001426:Bacterial Proteins; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology; D006801:Humans; D020014:K562 Cells; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D009705:Nucleosides / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000493:pharmacokinetics; D014157:Transcription Factors; D014529:Uridine / Q000493:pharmacokinetics; D048051:p38 Mitogen-Activated Protein Kinases
D051777:AraC Transcription Factor; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009705:Nucleosides; D012097:Repressor Proteins; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014529:Uridine