HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 32, 29509-29514, August 8, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/32/29509    most recent M304059200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guo, Y. Articles by Kruh, G. D. Search for Related Content PubMed PubMed Citation Articles by Guo, Y. Articles by Kruh, G. D. Social Bookmarking                      What's this?

MRP8, ATP-binding Cassette C11 (ABCC11), Is a Cyclic Nucleotide Efflux Pump and a Resistance Factor for Fluoropyrimidines 2',3'-Dideoxycytidine and 9'-(2'-Phosphonylmethoxyethyl)adenine^*

Yanping Guo, Elena Kotova, Zhe-Sheng Chen , Kun Lee, Elizabeth Hopper-Borge, Martin G. Belinsky and Gary D. Kruh 

From the Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

MRP8 (ABCC11) is a recently identified cDNA that has been assigned to the multidrug resistance-associated protein (MRP) family of ATP-binding cassette transporters, but its functional characteristics have not been determined. Here we examine the functional properties of the protein using transfected LLC-PK1 cells. It is shown that ectopic expression of MRP8 reduces basal intracellular levels of cAMP and cGMP and enhances cellular extrusion of cyclic nucleotides in the presence or absence of stimulation with forskolin or SIN-1A. Analysis of the sensitivity of MRP8-overexpressing cells revealed that they are resistant to a range of clinically relevant nucleotide analogs, including the anticancer fluoropyrimidines 5'-fluorouracil (3-fold), 5'-fluoro-2'-deoxyuridine (5-fold), and 5'-fluoro-5'-deoxyuridine (3-fold), the anti-human immunodeficiency virus agent 2',3'-dideoxycytidine (6-fold) and the anti-hepatitis B agent 9'-(2'-phosphonylmethoxynyl)adenine (PMEA) (5-fold). By contrast, increased resistance was not observed for several natural product chemotherapeutic agents. In accord with the notion that MRP8 functions as a drug efflux pump for nucleotide analogs, MRP8-transfected cells exhibited reduced accumulation and increased efflux of radiolabeled PMEA. In addition, it is shown by the use of in vitro transport assays that MRP8 is able to confer resistance to fluoropyrimidines by mediating the MgATP-dependent transport of 5'-fluoro-2'-deoxyuridine monophosphate, the cytotoxic intracellular metabolite of this class of agents, but not of 5'-fluorouracil or 5'-fluoro-2'-deoxyuridine. We conclude that MRP8 is an amphipathic anion transporter that is able to efflux cAMP and cGMP and to function as a resistance factor for commonly employed purine and pyrimidine nucleotide analogs.

Received for publication, April 17, 2003 , and in revised form, May 20, 2003.

^* This work was supported in part by NCI, National Institutes of Health, Grants CA73728 (to G. D. K.) and CA06927 and by an appropriation from the Commonwealth of Pennsylvania. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a W. J. Avery Fellowship from the Fox Chase Cancer Center and a Japan Research Foundation Award for Clinical Pharmacology.

To whom correspondence should be addressed. Tel: 215-728-5317; Fax: 215-728-3603; E-mail: GD_Kruh{at}fccc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Toyoda, A. Sakurai, Y. Mitani, M. Nakashima, K.-i. Yoshiura, H. Nakagawa, Y. Sakai, I. Ota, A. Lezhava, Y. Hayashizaki, et al. Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type? FASEB J, June 1, 2009; 23(6): 2001 - 2013. [Abstract] [Full Text] [PDF]

				S. Hauswald, J. Duque-Afonso, M. M. Wagner, F. M. Schertl, M. Lubbert, C. Peschel, U. Keller, and T. Licht Histone Deacetylase Inhibitors Induce a Very Broad, Pleiotropic Anticancer Drug Resistance Phenotype in Acute Myeloid Leukemia Cells by Modulation of Multiple ABC Transporter Genes Clin. Cancer Res., June 1, 2009; 15(11): 3705 - 3715. [Abstract] [Full Text] [PDF]

				Y. Guo, K. Kock, C. A. Ritter, Z.-S. Chen, M. Grube, G. Jedlitschky, T. Illmer, M. Ayres, J. F. Beck, W. Siegmund, et al. Expression of ABCC-Type Nucleotide Exporters in Blasts of Adult Acute Myeloid Leukemia: Relation to Long-term Survival Clin. Cancer Res., March 1, 2009; 15(5): 1762 - 1769. [Abstract] [Full Text] [PDF]

				E. Hopper-Borge, X. Xu, T. Shen, Z. Shi, Z.-S. Chen, and G. D. Kruh Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B Cancer Res., January 1, 2009; 69(1): 178 - 184. [Abstract] [Full Text] [PDF]

				H Nevala, T Ylikomi, and H Tahti Evaluation of the selected barrier properties of retinal pigment epithelial cell line ARPE-19 for an in-vitro blood-brain barrier model Human and Experimental Toxicology, October 1, 2008; 27(10): 741 - 749. [Abstract] [PDF]

				C. de Wolf, R. Jansen, H. Yamaguchi, M. de Haas, K. van de Wetering, J. Wijnholds, J. Beijnen, and P. Borst Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides Mol. Cancer Ther., September 1, 2008; 7(9): 3092 - 3102. [Abstract] [Full Text] [PDF]

				C. D. Cropp, T. Komori, J. E. Shima, T. J. Urban, S. W. Yee, S. S. More, and K. M. Giacomini Organic Anion Transporter 2 (SLC22A7) Is a Facilitative Transporter of cGMP Mol. Pharmacol., April 1, 2008; 73(4): 1151 - 1158. [Abstract] [Full Text] [PDF]

				M. Honorat, A. Mesnier, J. Vendrell, J. Guitton, I. Bieche, R. Lidereau, G. D Kruh, C. Dumontet, P. Cohen, and L. Payen ABCC11 expression is regulated by estrogen in MCF7 cells, correlated with estrogen receptor {alpha} expression in postmenopausal breast tumors and overexpressed in tamoxifen-resistant breast cancer cells Endocr. Relat. Cancer, March 1, 2008; 15(1): 125 - 138. [Abstract] [Full Text] [PDF]

				Z. P. Lin, Y.-L. Zhu, D. R. Johnson, K. P. Rice, T. Nottoli, B. C. Hains, J. McGrath, S. G. Waxman, and A. C. Sartorelli Disruption of cAMP and Prostaglandin E2 Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response Mol. Pharmacol., January 1, 2008; 73(1): 243 - 251. [Abstract] [Full Text] [PDF]

				D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [Abstract] [Full Text] [PDF]

				T. Oguri, Y. Bessho, H. Achiwa, H. Ozasa, K. Maeno, H. Maeda, S. Sato, and R. Ueda MRP8/ABCC11 directly confers resistance to 5-fluorouracil Mol. Cancer Ther., January 1, 2007; 6(1): 122 - 127. [Abstract] [Full Text] [PDF]

				S. Choudhuri and C. D. Klaassen Structure, Function, Expression, Genomic Organization, and Single Nucleotide Polymorphisms of Human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) Efflux Transporters International Journal of Toxicology, July 1, 2006; 25(4): 231 - 259. [Abstract] [Full Text] [PDF]

				R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]

				S. A. Andric, T. S. Kostic, and S. S. Stojilkovic Contribution of Multidrug Resistance Protein MRP5 in Control of Cyclic Guanosine 5'-Monophosphate Intracellular Signaling in Anterior Pituitary Cells Endocrinology, July 1, 2006; 147(7): 3435 - 3445. [Abstract] [Full Text] [PDF]

				S. Dallas, D. S. Miller, and R. Bendayan Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol. Rev., June 1, 2006; 58(2): 140 - 161. [Abstract] [Full Text] [PDF]

				J. M. Maher, A. L. Slitt, N. J. Cherrington, X. Cheng, and C. D. Klaassen TISSUE DISTRIBUTION AND HEPATIC AND RENAL ONTOGENY OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) FAMILY IN MICE Drug Metab. Dispos., July 1, 2005; 33(7): 947 - 955. [Abstract] [Full Text] [PDF]

				S. Pratt, R. L. Shepard, R. A. Kandasamy, P. A. Johnston, W. Perry III, and A. H. Dantzig The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites Mol. Cancer Ther., May 1, 2005; 4(5): 855 - 863. [Abstract] [Full Text] [PDF]

				Z.-S. Chen, Y. Guo, M. G. Belinsky, E. Kotova, and G. D. Kruh Transport of Bile Acids, Sulfated Steroids, Estradiol 17-{beta}-D-Glucuronide, and Leukotriene C4 by Human Multidrug Resistance Protein 8 (ABCC11) Mol. Pharmacol., February 1, 2005; 67(2): 545 - 557. [Abstract] [Full Text] [PDF]

				R. A. M. H. Van Aubel, P. H. E. Smeets, J. J. M. W. van den Heuvel, and F. G. M. Russel Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites Am J Physiol Renal Physiol, February 1, 2005; 288(2): F327 - F333. [Abstract] [Full Text] [PDF]

				M. Michael and M.M. Doherty Tumoral Drug Metabolism: Overview and Its Implications for Cancer Therapy J. Clin. Oncol., January 1, 2005; 23(1): 205 - 229. [Abstract] [Full Text] [PDF]

				J.-P. Annereau, G. Szakacs, C. J. Tucker, A. Arciello, C. Cardarelli, J. Collins, S. Grissom, B. R. Zeeberg, W. Reinhold, J. N. Weinstein, et al. Analysis of ATP-Binding Cassette Transporter Expression in Drug-Selected Cell Lines by a Microarray Dedicated to Multidrug Resistance Mol. Pharmacol., December 1, 2004; 66(6): 1397 - 1405. [Abstract] [Full Text] [PDF]

				H.-L. Xu, H. M. Wolde, V. Gavrilyuk, V. L. Baughman, and D. A. Pelligrino cAMP modulates cGMP-mediated cerebral arteriolar relaxation in vivo Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2501 - H2509. [Abstract] [Full Text] [PDF]

				E. Hopper-Borge, Z.-S. Chen, I. Shchaveleva, M. G. Belinsky, and G. D. Kruh Analysis of the Drug Resistance Profile of Multidrug Resistance Protein 7 (ABCC10): Resistance to Docetaxel Cancer Res., July 15, 2004; 64(14): 4927 - 4930. [Abstract] [Full Text] [PDF]

				S. Dallas, L. Schlichter, and R. Bendayan Multidrug Resistance Protein (MRP) 4- and MRP 5-Mediated Efflux of 9-(2-Phosphonylmethoxyethyl)adenine by Microglia J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1221 - 1229. [Abstract] [Full Text] [PDF]