Division of Hematology, SA Pathology, Adelaide, South Australia, Australia.
Leuk Lymphoma. 2013 Mar;54(3):569-78. doi: 10.3109/10428194.2012.715345. Epub 2012 Aug 21.
Imatinib and nilotinib interact with ABCB1 and ABCG2. However, whether they are substrates or inhibitors is a source of conjecture. Here, in vitro, Bcr-Abl kinase inhibition was used to elucidate the impact of ABCB1/ABCG2 overexpression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in a significantly increased 50% inhibitory concentration (IC(50)) compared with parental K562 cells for imatinib (IC(50)(IM); 9 µM to 19 µM, p = 0.002) and nilotinib (IC(50)(NIL); 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC(50)(IM) or IC(50)(NIL) or significantly decrease IC(50) upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150 nM but no increase when used at 2 µM. Imatinib and nilotinib appear to be transported by ABCB1 but do not interact strongly with ABCG2. Furthermore, ABCB1 efflux of nilotinib may be concentration-dependent with transport occurring at clinically relevant concentrations.
伊马替尼和尼罗替尼与 ABCB1 和 ABCG2 相互作用。然而，它们是底物还是抑制剂仍存在争议。在这里，我们通过体外实验，利用 Bcr-Abl 激酶抑制来阐明 ABCB1/ABCG2 过表达对伊马替尼和尼罗替尼转运的影响。K562-Dox 细胞中 ABCB1 蛋白水平较高，导致伊马替尼（IC50(IM)；9 µM 至 19 µM，p = 0.002）和尼罗替尼（IC50(NIL)；345 nM 至 620 nM，p = 0.013）的 50%抑制浓度（IC50）显著升高，与亲本 K562 细胞相比。这种差异可被 ABCB1 抑制剂消除。然而，ABCG2 的过表达并没有显著增加伊马替尼（IC50(IM)）或尼罗替尼（IC50(NIL)）的 IC50，也没有显著降低 ABCG2 抑制时的 IC50。抑制 ABCB1 但不抑制 ABCG2 可导致 150 nM 时细胞内尼罗替尼的含量显著增加，但 2 µM 时无增加。伊马替尼和尼罗替尼似乎通过 ABCB1 转运，但与 ABCG2 没有强烈相互作用。此外，尼罗替尼的 ABCB1 外排可能呈浓度依赖性，在临床相关浓度下发生转运。
