Abstract
Incomplete chemotherapeutic eradication of leukemic CD34+CD38− stem cells is likely to result in disease relapse. The purpose of this study was to evaluate the effect of nilotinib on eradicating leukemia stem cells and enhancing the efficacy of chemotherapeutic agents. Our results showed that ABCB1 and ABCG2 were preferentially expressed in leukemic CD34+CD38− cells. Nilotinib significantly enhanced the cytotoxicity of doxorubicin and mitoxantrone in CD34+CD38− cells and led to increased apoptosis. Moreover, nilotinib strongly reversed multidrug resistance and increased the intracellular accumulation of rhodamine 123 in primary leukemic blasts overexpressing ABCB1 and/or ABCG2. Studies with ABC transporter-overexpressing carcinoma cell models confirmed that nilotinib effectively reversed ABCB1- and ABCG2-mediated drug resistance, while showed no significant reversal effect on ABCC1- and ABCC4-mediated drug resistance. Results from cytotoxicity assays showed that CD34+CD38− cells exhibited moderate resistance (2.41-fold) to nilotinib, compared with parental K562 cells. Furthermore, nilotinib was less effective in blocking the phosphorylation of Bcr-Abl and CrkL (a substrate of Bcr-Abl kinase) in CD34+CD38− cells. Taken together, these data suggest that nilotinib particularly targets CD34+CD38− stem cells and MDR leukemia cells, and effectively enhances the efficacy of chemotherapeutic drugs by blocking the efflux function of ABC transporters.
Highlights
Intrinsic or treatment-induced acquired resistance is the major reason for therapeutic failure and an important cause of death in acute leukemia patients
Bcr-Abl kinase) in CD34+CD38− cells. These data suggest that nilotinib targets CD34+CD38− stem cells and multidrug resistance (MDR) leukemia cells, and effectively enhances the efficacy of chemotherapeutic drugs by blocking the efflux function of Molecules 2014, 19
In most of the studies investigating de novo or secondary adult acute myeloid leukemia (AML), ABCB1 (ATP-binding cassette superfamily member B1, P-glycoprotein) is an independent prognostic factor associated with reduced remission rates, and in some reports, inferior leukemia-free and overall survival [5,6,7]
Summary
Intrinsic or treatment-induced acquired resistance is the major reason for therapeutic failure and an important cause of death in acute leukemia patients. One of the best characterized resistance mechanisms is mediated by ATP-binding cassette (ABC) transporters which are capable of recognizing and extruding a broad range of structurally and functionally unrelated compounds [1,2,3,4]. An increasing number of ABC transporters have been shown to cause multidrug resistance (MDR) in leukemia patients. In most of the studies investigating de novo or secondary adult acute myeloid leukemia (AML), ABCB1 (ATP-binding cassette superfamily member B1, P-glycoprotein) is an independent prognostic factor associated with reduced remission rates, and in some reports, inferior leukemia-free and overall survival [5,6,7]. High expression of MRP genes is associated with a reduced relapse-free survival in acute lymphoblastic leukemia (ALL) patients and relapsed patients showed a higher expression of MRP genes [12]. ABCB1 expression in de novo adult ALL patients is an independent predictor of complete remission achievement [13]
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