Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606
Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606
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DOI：
10.1182/blood-2007-05-092056
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Bhatia, Ravi
中科院分区：
文献类型：
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作者：
Konig, Heiko;Holyoake, Tessa L.;Bhatia, Ravi
甲磺酸伊马替尼（伊马替尼）在治疗慢性粒细胞白血病（CML）方面非常有效，但在消除CIVIL干细胞方面效果较差。我们研究了SKI-606，一种没有抗PDGIF或c-Kit活性的有效Bcr-Abl和Src激酶抑制剂，是否可以有效靶向原始CML祖细胞。CML和正常祖细胞用SKI-606或伊马替尼培养。SKI-606能有效抑制CML CD 34（+）细胞中Bcr-Abl激酶活性，抑制Src磷酸化的作用强于伊马替尼。然而，SKI-606和伊马替尼在CFC和LTC-IC测定中对CML原始和定向祖细胞增殖和生长的抑制作用相似。暴露于单独或组合的任一药剂仅导致细胞凋亡的适度增加。下游信号通路的评估表明，Akt和STAT 5活性没有改变，但在高浓度的SKI-606中看到MAPK活性的延迟增加。SKI-606抑制正常祖细胞增殖的程度低于伊马替尼。SKI-606有效抑制Bcr-Abl和Src激酶活性，并抑制CML祖细胞生长，对正常祖细胞的影响相对较小。然而，与伊马替尼相比，SKI-606并没有表现出通过细胞凋亡消除原始CML祖细胞的能力增加，这强调了除了Bcr-Abl激酶抑制外，还需要其他策略来治愈CML。
Imatinib mesylate (imatinib) is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CIVIL stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGIF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34(+) cells and inhibited Src phosphorylation more potently than imatinib. However, SKI-606 and imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity was not changed, but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than imatinib. SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors. However, SKI-606 does not demonstrate increased ability to eliminate primitive CML progenitors by apoptosis compared with imatinib, emphasizing the need for additional strategies besides Bcr-Abl kinase inhibition for curative therapy of CML.