This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lorico, A. Articles by Sartorelli, A. C. Search for Related Content PubMed PubMed Citation Articles by Lorico, A. Articles by Sartorelli, A. C.

Double Knockout of the MRP Gene Leads to Increased Drug Sensitivity in Vitro¹

Department of Pharmacology and Developmental Therapeutics Program [A. L. G. R., A. C. S.] and Howard Hughes Medical Institute, Section of Immunobiology [R. A. F.] and Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

Overexpression of the multidrug resistance-associated protein (MRP) gene has been implicated in the resistance of tumor cell lines to a wide array of chemotherapeutic agents, but its normal physiological function(s) remains unknown. We have compared the sensitivity to chemotherapeutic drugs and toxins of wild-type W9.5 embryonic stem cells (ES) and of single and double MRP gene knockout cells derived therefrom. MRP expression was totally abrogated in the double knockout cell line and partially abrogated in the single knockout cell line. Reverse transcription-PCR analyses demonstrated that the MDR1, MDR2, and MDR3 genes were not expressed in either wild-type or MRP knock-out cells. The cytotoxic activities of etoposide, teniposide, vincristine, doxorubicin, daunorubicin, and sodium arsenite were significantly greater in double knockout cells than in parental wild-type ES cells; single knockout ES cells displayed an intermediate level of sensitivity. In contrast, no difference in sensitivity to colchicine and 1-ß-D-arabinofuranosylcytosine existed between the cell lines. Etoposide accumulation in double knockout ES cells was 2-fold higher than in wild-type ES cells. These findings indicate that baseline MRP expression has the capacity to exert a protective role against the toxicity of multiple chemotherapeutic agents and natural toxins.

¹ This research was supported in part by USPHS Grant CA-66739 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Yale University School of Medicine, Sterling Hall of Medicine, 333 Cedar Street, New Haven, CT 06520-8066. Phone: (203) 785-4533.

Received 8/23/96. Accepted 10/15/96.

This article has been cited by other articles:

				J. Leung, A. Pang, W.-H. Yuen, Y.-L. Kwong, and E. W. C. Tse Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells Blood, January 15, 2007; 109(2): 740 - 746. [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]

				M. Benlloch, A. Ortega, P. Ferrer, R. Segarra, E. Obrador, M. Asensi, J. Carretero, and J. M. Estrela Acceleration of Glutathione Efflux and Inhibition of {gamma}-Glutamyltranspeptidase Sensitize Metastatic B16 Melanoma Cells to Endothelium-induced Cytotoxicity J. Biol. Chem., February 25, 2005; 280(8): 6950 - 6959. [Abstract] [Full Text] [PDF]

				M. H. Mossink, A. van Zon, E. Franzel-Luiten, M. Schoester, V. A. Kickhoefer, G. L. Scheffer, R. J. Scheper, P. Sonneveld, and E. A. C. Wiemer Disruption of the Murine Major Vault Protein (MVP/LRP) Gene Does Not Induce Hypersensitivity to Cytostatics Cancer Res., December 15, 2002; 62(24): 7298 - 7304. [Abstract] [Full Text] [PDF]

				Z. P. Lin, D. R. Johnson, R. A. Finch, M. G. Belinsky, G. D. Kruh, and A. C. Sartorelli Comparative Study of the Importance of Multidrug Resistance-associated Protein 1 and P-Glycoprotein to Drug Sensitivity in Immortalized Mouse Embryonic Fibroblasts Mol. Cancer Ther., October 1, 2002; 1(12): 1105 - 1114. [Abstract] [Full Text] [PDF]

				D. R. Johnson, R. A. Finch, Z. P. Lin, C. J. Zeiss, and A. C. Sartorelli The Pharmacological Phenotype of Combined Multidrug-Resistance mdr1a/1b- and mrp1-deficient Mice Cancer Res., February 1, 2001; 61(4): 1469 - 1476. [Abstract] [Full Text]

				J. D. Allen, R. F. Brinkhuis, L. v. Deemter, J. Wijnholds, and A. H. Schinkel Extensive Contribution of the Multidrug Transporters P-Glycoprotein and Mrp1 to Basal Drug Resistance Cancer Res., October 1, 2000; 60(20): 5761 - 5766. [Abstract] [Full Text]

				P. Borst, R. Evers, M. Kool, and J. Wijnholds A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins J Natl Cancer Inst, August 16, 2000; 92(16): 1295 - 1302. [Abstract] [Full Text] [PDF]

				C. Dumontet and B. I. Sikic Mechanisms of Action of and Resistance to Antitubulin Agents: Microtubule Dynamics, Drug Transport, and Cell Death J. Clin. Oncol., March 1, 1999; 17(3): 1061 - 1061. [Abstract] [Full Text] [PDF]

				R. Advani, H. I. Saba, M. S. Tallman, J. M. Rowe, P. H. Wiernik, J. Ramek, K. Dugan, B. Lum, J. Villena, E. Davis, et al. Treatment of Refractory and Relapsed Acute Myelogenous Leukemia With Combination Chemotherapy Plus the Multidrug Resistance Modulator PSC 833 (Valspodar) Blood, February 1, 1999; 93(3): 787 - 795. [Abstract] [Full Text] [PDF]

				J. Dai, R. S. Weinberg, S. Waxman, and Y. Jing Malignant Cells Can Be Sensitized to Undergo Growth Inhibition and Apoptosis by Arsenic Trioxide Through Modulation of the Glutathione Redox System Blood, January 1, 1999; 93(1): 268 - 277. [Abstract] [Full Text] [PDF]

				K. Toth, M. M. Vaughan, G. Schwartz, J. S. Winston, B. S. Skenderis II, H. K. Slocum, and Y. M. Rustum Expression of the MRP and MDRI Multidrug Resistance Gene Products in 160 Untreated Human Carcinomas Studied by Immunohistochemical Methods in Formalin-Paraffin Sections International Journal of Surgical Pathology, July 1, 1998; 6(3): 145 - 154. [Abstract] [PDF]

				M.L. den Boer, R. Pieters, K.M. Kazemier, M.M.A. Rottier, C.M. Zwaan, G.J.L. Kaspers, G. Janka-Schaub, G. Henze, U. Creutzig, R.J. Scheper, et al. Relationship Between Major Vault Protein/Lung Resistance Protein, Multidrug Resistance-Associated Protein, P-Glycoprotein Expression, and Drug Resistance in Childhood Leukemia Blood, March 15, 1998; 91(6): 2092 - 2098. [Abstract] [Full Text] [PDF]