Although
arsenic trioxide (
arsenite, As(III)) 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 As(III). To test this hypothesis, stable HEK293 cells overexpressing MRP4 or MRP2 were used to establish the role of these two transporters in As(III) resistance. The IC50 values of As(III) in MRP4 cells were approximately 6-fold higher than those in MRP2 cells, supporting an important role for MRP4 in resistance to As(III). The capacity of MRP4 to confer resistance to As(III) 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 As(III) 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.