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Originally published In Press as doi:10.1074/jbc.C200321200 on June 20, 2002

J. Biol. Chem., Vol. 277, Issue 32, 28364-28367, August 9, 2002
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ACCELERATED PUBLICATION
Inhibition of Nucleoside Transport by p38 MAPK Inhibitors*

Min HuangDagger , Yanhong WangDagger , Matthew CollinsDagger , Jing Jin Gu§, Beverly S. Mitchell§, and Lee M. GravesDagger §

From the Dagger  Department of Pharmacology and the § Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599

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.

* This work was supported by National Institutes of Health Grant RO1-GM59767 and an American Heart Association established investigator grant (to L. M. G.), a Leukemia Research Foundation grant (to M. H.), and National Institutes of Health Grant RO1-CA34085 (to B. S. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology, 936 Mary Ellen Jones Bldg. CB# 7365, University of North Carolina, Chapel Hill, NC 27599-7365. Tel.: 919-966-0915; Fax: 919-966-5640; E-mail: lmg@med.unc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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