文章：

重新利用抗蠕虫药物以根除耐药性白血病

Repurposing anthelmintic agents to eradicate resistant leukemia

原文发布日期：2020-06-26

DOI: 10.1038/s41408-020-0339-9

类型: Article

开放获取: 是

英文摘要：

Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
 

摘要翻译： 

尽管急性淋巴细胞白血病（ALL）的基因组分析进展迅速，但可操作靶点的识别和药物反应预测仍然具有挑战性。为识别ALL中的特异性脆弱点，我们在模拟骨髓微环境的培养体系中结合高内涵图像分析，对原代人ALL样本进行了药物筛选。在测试的2487种FDA批准化合物中，大环内酯类驱虫药表现出与当前诱导化疗已知抗白血病药物相似的强效抗白血病活性。对55例原代ALL样本（包括前体B细胞和T细胞ALL及难治性复发病例）的体外验证证实，其具有强效抗白血病活性，IC50值处于低微摩尔浓度范围。驱虫药能增加原代白血病细胞的细胞内氯离子水平，诱导线粒体外膜去极化及细胞死亡。结合BCL-2拮抗剂navitoclax或化疗药物地塞米松后，在原发性ALL中显示出协同活性，这支持了从不同角度同时靶向细胞死亡机制可增强细胞死亡反应的观点。这些数据揭示了驱虫药的抗白血病活性，并支持利用药物再利用策略来识别迄今未被认识的、具有根除甚至难治性白血病潜力的抗癌药物。

原文链接：

Repurposing anthelmintic agents to eradicate resistant leukemia