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Takeuchi K, Shibata M, Kashiyama E, et al. Expression levels of multidrug resistance-associated protein 4 (MRP4) in human leukemia and lymphoma cell lines, and the inhibitory effects of the MRP-specific inhibitor MK-571 on methotrexate distribution in rats. Exp Ther Med. 2012;4(3):524-532doi: 10.3892/etm.2012.627.
Takeuchi, K., Shibata, M., Kashiyama, E., & Umehara, K. (2012). Expression levels of multidrug resistance-associated protein 4 (MRP4) in human leukemia and lymphoma cell lines, and the inhibitory effects of the MRP-specific inhibitor MK-571 on methotrexate distribution in rats. Experimental and therapeutic medicine, 4(3), 524-532. https://doi.org/10.3892/etm.2012.627
Takeuchi, Kenji, et al. "Expression levels of multidrug resistance-associated protein 4 (MRP4) in human leukemia and lymphoma cell lines, and the inhibitory effects of the MRP-specific inhibitor MK-571 on methotrexate distribution in rats." Experimental and therapeutic medicine vol. 4,3 (2012): 524-532. doi: https://doi.org/10.3892/etm.2012.627
Takeuchi K, Shibata M, Kashiyama E, Umehara K. Expression levels of multidrug resistance-associated protein 4 (MRP4) in human leukemia and lymphoma cell lines, and the inhibitory effects of the MRP-specific inhibitor MK-571 on methotrexate distribution in rats. Exp Ther Med. 2012 Sep;4(3):524-532. doi: 10.3892/etm.2012.627. Epub 2012 Jun 29. PMID: 23181130; PMCID: PMC3503844.
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Exp Ther Med. 2012 Sep;4(3):524-532. doi: 10.3892/etm.2012.627. Epub 2012 Jun 29.

Expression levels of multidrug resistance-associated protein 4 (MRP4) in human leukemia and lymphoma cell lines, and the inhibitory effects of the MRP-specific inhibitor MK-571 on methotrexate distribution in rats.

Experimental and therapeutic medicine

Kenji Takeuchi, Masakazu Shibata, Eiji Kashiyama, Ken Umehara

Affiliations

  1. Department of Drug Metabolism, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima 771-0192, Japan.

PMID: 23181130 PMCID: PMC3503844 DOI: 10.3892/etm.2012.627

Abstract

In the development of anti-blood cancer drugs, the chronic myelocytic leukemia (KU812), acute myelocytic leukemia (KG-1) and lymphoma (U937) cell lines are commonly used in preclinical pharmacology studies as human cancer xenograft models in mice. In the present study, mRNA expression levels of typical human ATP-binding cassette (ABC) transporters in these human blood cancer cell lines were analyzed by real-time polymerase chain reaction (RT-PCR). Based on the results, the expression level of multidrug resistance-associated protein 4 (MRP4) was found to be extremely high in KU812 cells compared with those of other transporters. Additionally, MRP4 expression levels were found to be relatively high in U937, KG-1 and a blood cell line derived from a healthy subject (RPMI 1788). In addition, to elucidate the contribution of MRP4 to the methotrexate (MTX) distribution in normal blood cells and tissues, [(3)H]MTX was intravenously (i.v.) administered to two groups of rats. Animals in one group received [(3)H]MTX only; the other group was concomitantly administered i.v. MK-571, a typical inhibitor of MRP transporters. No marked difference was observed between the two groups; the Kp values (tissue concentration/plasma concentration) of the concomitant group showed slightly higher values compared with those of the MTX alone group in erythrocytes (1.4 times, P<0.001), spleen (1.3 times, P<0.05) and thymus (1.2 times, P<0.05), respectively. Although in the present study we could not evaluate the direct involvement of MRP4 in blood cancer cells in which MRP4 expression was excessively high, these results suggest a possible functional role of MRP4 in blood cancer cells and albeit only slightly in normal blood cells/tissues.

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