Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells
Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells
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DOI：
10.1182/blood-2006-11-057521
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发表时间：
2007-05-01
期刊：
影响因子：
20.3
通讯作者：
Holyoake, Tessa L.
中科院分区：
文献类型：
--
作者：
Jorgensen, Heather G.;Allan, Elaine K.;Holyoake, Tessa L.
慢性髓性白血病（CML）干细胞和祖细胞过表达BcrAbl，对甲磺酸伊马替尼（IM）不敏感。因此，我们研究了尼洛替尼是否有效靶向这些细胞。在K562中，尼洛替尼的抑制浓度（IC 50）为30 nM，而IM为600 nM，与报告的20倍效价一致。然而，在原代CD 34（+）CML细胞中，尼洛替尼和IM对BcrAbl活性的抑制作用相同，在5 μ M浓度下，CrkL磷酸化水平降低相当但不完全。CML CD 34+细胞在5 μ M的任一药物下仍能扩增72小时以上，尽管存在浓度依赖性扩增限制。对于IM，尼洛替尼组最原始的细胞（CFSEmax）持续存在并累积超过72小时，并且保持caspase-3阴性。此外，尼洛替尼联合IM导致该人群的进一步蓄积，表明至少具有累加性抗增殖作用。这些结果证实，与IM一样，尼洛替尼的主要作用是抗增殖而非促凋亡。
Chronic myeloid leukemia (CML) stem and progenitor cells overexpress BcrAbl and are insensitive to imatinib mesylate (IM). We therefore investigated whether these cells were efficiently targeted by nilotinib. In K562, the inhibitory concentration (IC50) of nilotinib was 30 nM versus 600 nM for IM, consistent with its reported 20-fold-higher potency. However, in primary CD34(+) CML cells, nilotinib and IM were equipotent for inhibition of BcrAbl activity, producing equivalent but incomplete reduction in CrkL phosphorylation at 5 mu M. CML CD34+ cells were still able to expand over 72 hours with 5 mu M of either drug, although there was a concentration-dependent restriction of amplification. As for IM, the most primitive cells (CFSEmax) persisted and accumulated over 72 hours with nilotinib and remained caspase-3 negative. Furthermore, nilotinib with IM led to further accumulation of this population, suggesting at least additive antiproliferative effects. These results confirmed that, like IM, the predominant effect of nilotinib is antiproliferative rather than proapoptotic.