Tetrandrine antagonizes acute megakaryoblastic leukaemia growth by forcing autophagy-mediated differentiation
Tetrandrine antagonizes acute megakaryoblastic leukaemia growth by forcing autophagy-mediated differentiation
复制标题
粉防己碱通过强制自噬介导的分化来拮抗急性巨核细胞白血病的生长
DOI：
10.1111/bph.14031
复制
发表时间：
2017-12-01
影响因子：
7.3
通讯作者：
Li, Wenhua
中科院分区：
文献类型：
--
作者：
Liu, Ting;Zhang, Zhenxing;Li, Wenhua
背景与目的急性巨核细胞白血病(AMKL)预后较差，需要开发新的治疗方法。最近的研究表明，诱导巨核细胞进行终末分化是治疗AMKL的有效方法。这促使我们确定了一种诱导巨核细胞分化的化合物，它可以作为一种有效的抗白血病药物。实验方法研究粉防己碱对AMKL细胞CD41表达和细胞形态的影响。我们使用CRISPR/Cas9基因敲除系统敲除ATG7，验证自噬在粉防己碱诱导巨核细胞分化中的作用。将shNotch1和CA-Akt分别导入K562细胞，研究ROS信号的下游通路以及粉防己碱诱导巨核细胞分化的机制。结果小剂量粉防己碱通过激活自噬诱导AMKL细胞周期停滞和巨核细胞分化。在分子水平上，我们证明了这种作用是通过激活Notch1和Akt以及随后的ROS积累来实现的。相比之下，在正常小鼠胎肝细胞中，粉防己碱虽然诱导自噬，但不影响细胞增殖或促进巨核细胞分化，提示粉防己碱对恶性巨核细胞具有特异性作用。结论和应用调节自噬介导的分化可能是治疗AMKL的一种新策略，粉防己碱有可能作为AMKL化疗的分化诱导剂。
BACKGROUND AND PURPOSEThe poor prognosis of acute megakaryoblastic leukaemia (AMKL) means there is a need to develop novel therapeutic methods to treat this condition. It was recently shown that inducing megakaryoblasts to undergo terminal differentiation is effective as a treatment for AMKL. This encouraged us to identify a compound that induces megakaryocyte differentiation, which could then act as a potent anti-leukaemia agent.EXPERIMENTAL APPROACHThe effects of tetrandrine on the expression of CD41 and cell morphology were investigated in AMKL cells. We used CRISPR/Cas9 knockout system to knock out ATG7 and verify the role of autophagy in tetrandrine-induced megakaryocyte differentiation. shNotch1 and CA-Akt were transfected into K562 cells to examine the downstream pathways of ROS signalling and the mechanistic basis of the tetrandrine-induced megakaryocyte differentiation. The anti-leukaemia effects of tetrandrine were analysed both in vitro and in vivo.KEY RESULTSA low dose of tetrandrine induced cell cycle arrest and megakaryocyte differentiation in AMKL cells via activation of autophagy. Molecularly, we demonstrated that this effect is mediated by activation of Notch1 and Akt and subsequent accumulation of ROS. In contrast, in normal mouse fetal liver cells, although tetrandrine induced autophagy, it did not affect cell proliferation or promote megakaryocyte differentiation, suggesting a specific effect of tetrandrine in malignant megakaryoblasts. Finally, tetrandrine also showed in vivo efficacy in an AMKL xenograft mouse model.CONCLUSIONS AND IMPLICATIONSModulating autophagy-mediated differentiation may be a novel strategy for treating AMKL, and tetrandrine has the potential to be developed as a differentiation-inducing agent for AMKL chemotherapy.