chronic myeloid leukaemia Transporter 1 (hOCT1): implications for the treatment of imatinib resistant Effective dasatinib uptake may occur without human organic Cation

ABSTRACT We have previously shown that imatinib uptake into chronic myeloid leukaemia (CML) cells is dependent on human Organic Cation Transporter 1 (hOCT1; SLC22A1), and that low hOCT1 expression is an important determinant of clinical outcome to imatinib treatment. We hypothesised that dasatinib might be transported differently to imatinib, possibly accounting for its favourable effects in imatinib-resistant patients. 14 C-dasatinib uptake was greater in KCL22-transfected cells with pcDNA3-hOCT1 plasmid (high-hOCT1 expressing cells) than in control cells (p=0.02). However, hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells, in contrast to their block on imatinib uptake. Dasatinib decreased the level of phosphorylated CrkL to 49.9% in control and 40.3% in high-hOCT1 expressing cells. Dasatinib efflux was investigated in confluent ABCB1-transfected MDCKII cell monolayers. Both dasatinib and imatinib were transported from the basal to the apical layer indicating that they were transported by ABCB1, which was confirmed by using the ABCB1 inhibitor PSC833 (p=0.001 and p<0.0001 respectively). Compared with imatinib, dasatinib achieved superior intracellular levels and BCR-ABL suppression even in cells with low or blocked hOCT1. Efflux of dasatinib and imatinib appear similar via ABCB1. Dasatinib may therefore offer an advantage over imatinib in patients with low hOCT1 expression. From bloodjournal.hematologylibrary.org by guest on June 10, 2013. For personal use only.