Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1
Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1
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DOI：
10.1038/leu.2011.2
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发表时间：
2011-05-01
期刊：
影响因子：
11.4
通讯作者：
Ringshausen, I.
中科院分区：
文献类型：
--
作者：
Huber, S.;Oelsner, M.;Ringshausen, I.
慢性淋巴细胞白血病（CLL）在西方国家的发病率很高，至今仍无法治愈。在这里，我们提供的证据表明，多激酶抑制剂索拉非尼诱导原代CLL细胞凋亡。基于Binet分期和ZAP 70或CD 38的表达，这种强烈的促凋亡作用不限于任何亚组的患者。在机制上，索拉非尼诱导的细胞死亡之前，通过抑制蛋白质翻译快速下调Mcl-1。随后，细胞内在凋亡途径被激活，这通过线粒体膜电位的不稳定和半胱天冬酶-3和-9的激活来指示。与索拉非尼相反，单克隆血管表皮生长因子（VEGF）-抗体贝伐单抗未能诱导CLL细胞凋亡，表明索拉非尼诱导细胞死亡与VEGF信号无关。值得注意的是，尽管索拉非尼抑制Scr-激酶Lck的磷酸化，但Lck的敲低并不诱导CLL细胞的凋亡。值得注意的是，索拉非尼的促凋亡作用不限于细胞周期停滞的细胞，而且在增殖的CLL细胞中也得以维持。此外，我们提供的证据表明，索拉非尼可以克服CLL细胞的耐药性保护的微环境信号从基质细胞。结论：索拉非尼对慢性淋巴细胞白血病具有高度的治疗活性，可能为免疫化疗后复发的患者提供一种新的治疗选择。Leukemia（2011）25，838-847; doi：10.1038/leu.2011.2; 2011年2月4日在线发表
Chronic lymphocytic leukemia (CLL) has a high prevalence in western countries and remains incurable to date. Here, we provide evidence that the multikinase inhibitor sorafenib induces apoptosis in primary CLL cells. This strong proapoptotic effect is not restricted to any subgroup of patients, based on Binet stage and the expression of ZAP70 or CD38. Mechanistically, sorafenib-induced cell death is preceded by a rapid downregulation of Mcl-1 through the inhibition of protein translation. Subsequently, the cell intrinsic apoptotic pathway is activated, indicated by destabilization of the mitochondrial membrane potential and activation of caspase-3 and -9. In contrast to sorafenib, the monoclonal vascular epidermal growth factor (VEGF)-antibody bevacizumab failed to induce apoptosis in CLL cells, suggesting that sorafenib induces cell death irrespectively of VEGF signalling. Notably, although sorafenib inhibits phosphorylation of the Scr-kinase Lck, knock-down of Lck did not induce apoptosis in CLL cells. Of note, the pro-apoptotic effect of sorafenib is not restricted to cell-cycle arrested cells, but is also maintained in proliferating CLL cells. In addition, we provide evidence that sorafenib can overcome drug resistance in CLL cells protected by microenvironmental signals from stromal cells. Conclusively, sorafenib is highly active in CLL and may compose a new therapeutic option for patients who relapse after immunochemotherapy. Leukemia (2011) 25, 838-847; doi: 10.1038/leu.2011.2; published online 4 February 2011