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

  • Authors:
    • Kenji Takeuchi
    • Masakazu Shibata
    • Eiji Kashiyama
    • Ken Umehara
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  • Published online on: June 29, 2012     https://doi.org/10.3892/etm.2012.627
  • Pages: 524-532
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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, [3H]MTX was intravenously (i.v.) administered to two groups of rats. Animals in one group received [3H]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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September 2012
Volume 4 Issue 3

Print ISSN: 1792-0981
Online ISSN:1792-1015

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Spandidos Publications style
Takeuchi K, Shibata M, Kashiyama E and 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 4: 524-532, 2012
APA
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, 524-532. https://doi.org/10.3892/etm.2012.627
MLA
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". Experimental and Therapeutic Medicine 4.3 (2012): 524-532.
Chicago
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". Experimental and Therapeutic Medicine 4, no. 3 (2012): 524-532. https://doi.org/10.3892/etm.2012.627