Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells
Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells
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DOI：
10.1038/sj.leu.2404638
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发表时间：
2007-06-01
期刊：
影响因子：
11.4
通讯作者：
Neubauer, A.
中科院分区：
文献类型：
--
作者：
Brendel, C.;Scharenberg, C.;Neubauer, A.
大多数接受酪氨酸激酶抑制剂甲磺酸伊马替尼治疗的慢性期慢性髓性白血病（CML）患者对该药物保持持久的反应。然而，大多数患者在停用伊马替尼后复发，晚期患者常常产生耐药性。由于慢性髓性白血病被认为是一种造血干细胞癌症，据推测内在的保护机制导致患者复发。ATP结合盒转运体ABCB1（MDR - 1；P - 糖蛋白）和ABCG2在原始造血干细胞（HSCs）上高度表达，并已被证明与酪氨酸激酶抑制剂相互作用。在此我们证明伊马替尼和尼罗替尼（AMN107，一种新型的BCR - ABL氨基嘧啶抑制剂）对原代人类和小鼠造血干细胞中ABCG2介导的Hoechst 33342染料外排具有剂量依赖性的可逆抑制作用。ABCG2转导的K562细胞免受伊马替尼和尼罗替尼介导的细胞死亡以及P - CRKL的下调。此外，光亲和标记显示两种酪氨酸激酶抑制剂在底物结合位点与ABCG2相互作用，因为它们与[I - 125] IAAP的结合竞争，并且还刺激转运体的ATP酶活性。因此，我们的证据表明ABC转运体在原始造血干细胞和慢性髓性白血病干细胞对酪氨酸激酶抑制剂耐药中起作用，并为如何在体内克服酪氨酸激酶抑制剂耐药提供了理论依据。
The majority of chronic phase chronic myeloid leukemia (CML) patients treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate maintain durable responses to the drug. However, most patients relapse after withdrawal of imatinib and advanced stage patients often develop drug resistance. As CML is considered a hematopoietic stem cell cancer, it has been postulated that inherent protective mechanisms lead to relapse in patients. The ATP binding-cassette transporters ABCB1 (MDR-1; P-glycoprotein) and ABCG2 are highly expressed on primitive hematopoietic stem cells (HSCs) and have been shown to interact with TKIs. Herein we demonstrate a dose-dependent, reversible inhibition of ABCG2-mediated Hoechst 33342 dye efflux in primary human and murine HSC by both imatinib and nilotinib (AMN107), a novel aminopyrimidine inhibitor of BCR-ABL. ABCG2-transduced K562 cells were protected from imatinib and nilotinib-mediated cell death and from downregulation of P-CRKL. Moreover, photoaffinity labeling revealed interaction of both TKIs with ABCG2 at the substrate binding sites as they compete with the binding of [I-125] IAAP and also stimulate the transporter's ATPase activity. Therefore, our evidence suggests for the role of ABC transporters in resistance to TKI on primitive HSCs and CML stem cells and provides a rationale how TKI resistance can be overcome in vivo.