文章：

患者细胞中的药物筛选提示奎纳克林可重新用于治疗急性髓系白血病

Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

原文发布日期：2015-04-17

DOI: 10.1038/bcj.2015.31

类型: Original Article

开放获取: 是

英文摘要：

To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.

摘要翻译： 

为寻找适用于白血病治疗的药物再利用方案，研究人员对来自慢性淋巴细胞白血病、急性髓系白血病和淋巴细胞白血病患者的样本以及外周血单核细胞（PBMC）进行了测试，使用LOPAC1280化合物库（西格玛公司）中的1266种化合物进行筛选。在10μM药物浓度下，有25种化合物被定义为在所有白血病亚组中均具有活性（与对照组相比细胞存活率<50%）。这些化合物中仅有奎纳克林在正常PBMCs中表现出较低活性，因此被选中进行进一步的临床前评估。通过挖掘NCI-60和NextBio数据库，研究证实了奎纳克林对白血病的敏感性及其逆转髓系白血病基因表达的能力。利用NextBio生物信息学软件，对数据库中经药物处理的急性髓系白血病培养细胞（HL-60）进行基因表达分析，开展了机制探索。基因富集和药物相关性分析显示，该药物与核糖体生物发生核仁及翻译起始具有强关联性。最高的药物相关性来自椭圆玫瑰树碱（一种已知的RNA聚合酶I抑制剂）。这些结果通过内部进行的额外基因表达分析得到验证。奎纳克林能早期抑制蛋白质合成，支持了上述预测。结果表明，通过靶向核糖体生物发生，奎纳克林具有治疗急性髓系白血病的再利用潜力。

原文链接：

Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia