P8.04 - Comparison of Human Nucleoside Transporter Interactions with BCR-ABL Kinase Inhibitors

Abstract

ABSTRACT Introduction: Human nucleoside transporters (hNTs) regulate cellular influx and disposition of anticancer nucleoside drugs. Cytarabine and fludarabine uptake in leukemic cells, which occurs primarily via human nucleoside transporter 1 (hENT1), was shown to be inhibited by imatinib and nilotinib [ 1 , 2 ]. We studied interactions of the BCR-ABL kinase inhibitors bosutinib, dasatinib, imatinib, nilotinib and ponatinib with five human nucleoside transporters (hENT1-2 and hCNT1-3) that mediate cellular uptake of various anticancer nucleoside drugs. Materials and methods: hNT interactions with bosutinib, dasatinib, imatinib, nilotinib and ponatinib were assessed by comparing their relative abilities to inhibit [3H]uridine uptake in yeast producing each of the recombinant hNTs individually. Inhibition of [3H]uridine, [3H]cytarabine, [3H]fludarabine and [3H]cladribine uptake and long-term accumulation was examined in the CEM cell line. Inhibition of [3H]uridine uptake was also studied in the K562 and KG1 cell lines. Results: BCR-ABL TKIs inhibited recombinant yeast hENT1 and hENT2 with some inhibiting more than others. One or more hCNTs was inhibited by bosutinib, ponatinib, dasatinib and imatinib whereas nilotinib had no effect. In CEM cells (possess only hENT1) nilotinib inhibited hENT1 most potently followed by bosutinib, ponatinib, dasatinib and imatinib with IC50 values of ± 0.7, 2.0, 3.0, 8 and 16 µM, respectively. Accumulation of [3H]cytarabine, cladribine and fludarabine in CEM cells was inhibited by all five BCR-ABL TKIs. Experiments are underway to figure out mechanisms of hNT inhibition by these TKIs. Conclusions: All five BCR-ABL TKIs inhibited hENT1 and hENT2 to different extent leading to reduced intracellular nucleoside accumulation. In addition at least one or more hCNTs were inhibited except by nilotinib. acknowledgements: This research was funded by the Alberta Cancer Board Research Initiative Program (M.B.S., C.E.C), and the Canadian Cancer Society Research Institute (C.E.C.).