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Article

Multidrug resistance-associated protein 4 is a determinant of arsenite resistance

  • Authors:
    • Bo Yuan
    • Yuta Yoshino
    • Hisayo Fukushima
    • Svetlana Markova
    • Norio Takagi
    • Hiroo Toyoda
    • Deanna L. Kroetz
  • View Affiliations / Copyright

    Affiliations: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94143, USA, Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan, Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
  • Pages: 147-154
    |
    Published online on: October 22, 2015
       https://doi.org/10.3892/or.2015.4343
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Abstract

Although arsenic trioxide (arsenite, AsIII) has shown a remarkable efficacy in the treatment of acute promyelocytic leukemia patients, multidrug resistance is still a major concern for its clinical use. Multidrug resistance-associated protein 4 (MRP4), which belongs to the ATP-binding cassette (ABC) superfamily of transporters, is localized to the basolateral membrane of hepatocytes and the apical membrane of renal proximal tubule cells. Due to its characteristic localization, MRP4 is proposed as a candidate in the elimination of arsenic and may contribute to resistance to AsIII. To test this hypothesis, stable HEK293 cells overexpressing MRP4 or MRP2 were used to establish the role of these two transporters in AsIII resistance. The IC50 values of AsIII in MRP4 cells were approximately 6-fold higher than those in MRP2 cells, supporting an important role for MRP4 in resistance to AsIII. The capacity of MRP4 to confer resistance to AsIII was further confirmed by a dramatic decrease in the IC50 values with the addition of MK571, an MRP4 inhibitor, and cyclosporine A, a well-known broad-spectrum inhibitor of ABC transporters. Surprisingly, the sensitivity of the MRP2 cells to AsIII was similar to that of the parent cells, although insufficient formation of glutathione and/or Se conjugated arsenic compounds in the MRP2 cells might limit transport. Given that MRP4 is a major contributor to arsenic resistance in vitro, further investigation into the correlation between MRP4 expression and treatment outcome of leukemia patients treated with arsenic-based regimens is warranted.
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Copy and paste a formatted citation
Spandidos Publications style
Yuan B, Yoshino Y, Fukushima H, Markova S, Takagi N, Toyoda H and Kroetz DL: Multidrug resistance-associated protein 4 is a determinant of arsenite resistance. Oncol Rep 35: 147-154, 2016.
APA
Yuan, B., Yoshino, Y., Fukushima, H., Markova, S., Takagi, N., Toyoda, H., & Kroetz, D.L. (2016). Multidrug resistance-associated protein 4 is a determinant of arsenite resistance. Oncology Reports, 35, 147-154. https://doi.org/10.3892/or.2015.4343
MLA
Yuan, B., Yoshino, Y., Fukushima, H., Markova, S., Takagi, N., Toyoda, H., Kroetz, D. L."Multidrug resistance-associated protein 4 is a determinant of arsenite resistance". Oncology Reports 35.1 (2016): 147-154.
Chicago
Yuan, B., Yoshino, Y., Fukushima, H., Markova, S., Takagi, N., Toyoda, H., Kroetz, D. L."Multidrug resistance-associated protein 4 is a determinant of arsenite resistance". Oncology Reports 35, no. 1 (2016): 147-154. https://doi.org/10.3892/or.2015.4343
Copy and paste a formatted citation
x
Spandidos Publications style
Yuan B, Yoshino Y, Fukushima H, Markova S, Takagi N, Toyoda H and Kroetz DL: Multidrug resistance-associated protein 4 is a determinant of arsenite resistance. Oncol Rep 35: 147-154, 2016.
APA
Yuan, B., Yoshino, Y., Fukushima, H., Markova, S., Takagi, N., Toyoda, H., & Kroetz, D.L. (2016). Multidrug resistance-associated protein 4 is a determinant of arsenite resistance. Oncology Reports, 35, 147-154. https://doi.org/10.3892/or.2015.4343
MLA
Yuan, B., Yoshino, Y., Fukushima, H., Markova, S., Takagi, N., Toyoda, H., Kroetz, D. L."Multidrug resistance-associated protein 4 is a determinant of arsenite resistance". Oncology Reports 35.1 (2016): 147-154.
Chicago
Yuan, B., Yoshino, Y., Fukushima, H., Markova, S., Takagi, N., Toyoda, H., Kroetz, D. L."Multidrug resistance-associated protein 4 is a determinant of arsenite resistance". Oncology Reports 35, no. 1 (2016): 147-154. https://doi.org/10.3892/or.2015.4343
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