Intracellular Retention of ABL Kinase Inhibitors Determines Commitment to Apoptosis in CML Cells
Intracellular Retention of ABL Kinase Inhibitors Determines Commitment to Apoptosis in CML Cells
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DOI：
10.1371/journal.pone.0040853
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发表时间：
2012-07-16
期刊：
影响因子：
3.7
通讯作者：
Fischer, Thomas
中科院分区：
文献类型：
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作者：
Lipka, Daniel B.;Wagner, Marie-Christine;Fischer, Thomas
伊马替尼在慢性粒细胞白血病中的临床发展确立了持续靶点抑制作为成功的酪氨酸激酶抑制剂(TKI)治疗的范例。然而，最近的报道表明，大剂量TKI(HD-TKI)脉冲照射对BCR-ABL的瞬时有效靶向抑制足以不可逆转地使细胞发生凋亡。在这里，我们报告了一种新的机制，延长细胞内TKI活性的HD-TKI脉冲暴露(伊马替尼，达沙替尼)在BCR-ABL阳性细胞。全面的机制探索揭示了TKI在细胞内的大量积聚，这与诱导细胞凋亡密切相关。在HD-TKI脉冲作用下，通过重复药物洗脱或ABC家族药物转运蛋白的过表达，细胞从凋亡中拯救出来。抑制ABCB1可恢复对HD-TKI脉冲照射的敏感性。因此，我们的数据提供了证据，证明细胞内药物保留至关重要地决定了伊马替尼和达沙替尼的生物活性。这些研究可能会完善我们目前对TKI剂量和靶向抑制持续时间对TKI生物活性的关键要求的思考。
Clinical development of imatinib in CML established continuous target inhibition as a paradigm for successful tyrosine kinase inhibitor (TKI) therapy. However, recent reports suggested that transient potent target inhibition of BCR-ABL by high-dose TKI (HD-TKI) pulse-exposure is sufficient to irreversibly commit cells to apoptosis. Here, we report a novel mechanism of prolonged intracellular TKI activity upon HD-TKI pulse-exposure (imatinib, dasatinib) in BCR-ABL-positive cells. Comprehensive mechanistic exploration revealed dramatic intracellular accumulation of TKIs which closely correlated with induction of apoptosis. Cells were rescued from apoptosis upon HD-TKI pulse either by repetitive drug wash-out or by overexpression of ABC-family drug transporters. Inhibition of ABCB1 restored sensitivity to HD-TKI pulse-exposure. Thus, our data provide evidence that intracellular drug retention crucially determines biological activity of imatinib and dasatinib. These studies may refine our current thinking on critical requirements of TKI dose and duration of target inhibition for biological activity of TKIs.