Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells

Arsenic trioxide (As2O3) is established as one of the most effective drugs for treatment of patients with acute promyelocytic leukemia, as well as other types of malignant tumors. However, HL-60 cells are resistant to As2O3, and little is known about the underlying resistance mechanism for As2O3 and its biomethylation products, namely, monomethylarsonous acid (MMAIII) on the treatment of tumors. In the present study, we investigated the molecular mechanisms underlying iAsIII and its intermediate metabolite MMAIII-induced anticancer effects in the HL-60 cells. Here, we show that the HL-60 cells exhibit resistance to inorganic iAsIII (IC50 = 10 μM), but are relatively sensitive to its intermediate MMAIII (IC50 = 3.5 μM). Moreover, we found that the multidrug resistance protein 1 (MRP1), but not MRP2, is expressed in HL-60 cells, which reduced the intracellular arsenic accumulation, and conferred resistance to inorganic iAsIII and MMAIII. Pretreatment of HL-60 with MK571, an inhibitor of MRP1, significantly increased iAsIII and MMAIII-induced cytotoxicity and arsenic accumulations, suggesting that the expression of MRP1/4 may lead to HL-60 cells resistance to trivalent arsenic compounds.