Abstract
Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25–30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity. MATE1 mainly mediates the cellular uptake of imatinib into targeted cells and thereby controls the intracellular effectiveness of imatinib. Importantly, MATE1 but not OCT1 expression is reduced in total bone marrow cells of imatinib-non-responding CML patients compared with imatinib-responding patients, indicating that MATE1 but not OCT1 determines the therapeutic success of imatinib. We thus propose that imatinib non-responders could be identified early before starting therapy by measuring MATE1 expression levels.
Highlights
The tyrosine kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), some patients do not respond to imatinib or relapse after initial response.[1,2]
Imatinib uptake as detected by HPLC was significantly increased in organic cation transporter 1 (OCT1)- (1.16 ± 0.16 nmol/mg protein; P = 0.0013), OCT2- (1.30 ± 0.13 nmol/mg protein; P = 0.0001) and multidrug and toxin extrusion protein 1 (MATE1)-overexpressing HEK cells (1.16 ± 0.15 nmol/mg protein; P = 0.0002), but not in OCT3-HEK cells
MATE1mediated transport was inhibited by 200 nM pyrimethamine (SigmaAldrich, Steinheim, Germany),[20] whereas 80 μM MPP+ (Sigma-Aldrich) was used for OCT1 and OCT2 coinhibition.[14,20–23]
Summary
The tyrosine kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), some patients do not respond to imatinib or relapse after initial response.[1,2] In all, 25–30% of CML patients treated with imatinib as a first-line therapy experience treatment failure leading to an increased risk of progression to accelerated or blast phase. Some studies suggested a critical role of OCT1 in regulating imatinib efficacy,[5,6,7] other studies could not confirm these findings.[8,9] The role of OCT1 for imatinib uptake has mostly been inferred from inhibition studies with prazosin and amantadine. This approach has been criticized recently, as these substances do not inhibit OCT1 but are potential inhibitors of other imatinib uptake pathways distinct from OCT1.10 OCT1 is generally capable to transport imatinib, it might have minor relevance for a transport under clinical conditions. Experiments on model cells have shown that other members of this group transport imatinib.[11,12,15] Others and our group recently demonstrated that the multidrug and toxin extrusion protein 1 (MATE1), belonging to the group of organic cation transporters, accepts imatinib as a substrate.[11,12]
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