Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia.
Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia.
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DOI：
10.1038/bcj.2015.31
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发表时间：
2015-04-17
影响因子：
12.8
通讯作者：
Larsson R
中科院分区：
文献类型：
--
作者：
Eriksson A;Österroos A;Hassan S;Gullbo J;Rickardson L;Jarvius M;Nygren P;Fryknäs M;Höglund M;Larsson R
为了找到适合于重新定位以用于抗白血病的药物，测试了来自慢性淋巴细胞性、急性骨髓性和淋巴细胞性白血病患者以及外周血单核细胞（PBMC）的样品对来自LOPAC 1280文库（Sigma）的1266种化合物的响应。25种化合物被定义为在10 μM药物浓度下在所有白血病亚组中具有活性的命中物（与对照相比<50%细胞存活）。这些化合物中只有一种，奎纳克林，在正常PBMC中显示出低活性，因此被选择用于进一步的临床前评价。对NCI-60和NextBio数据库的挖掘证明了白血病的敏感性和奎纳克林逆转骨髓性白血病基因表达的能力。使用NextBio生物信息学软件，使用数据库中药物暴露的急性髓性白血病培养物（HL-60）的基因表达分析进行机制探索。基因富集和药物相关性的分析显示了与核糖体生物发生、核仁和翻译起始的密切联系。药物间相关性最高的是椭圆树碱，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进行了验证。奎纳克林诱导蛋白质合成的早期抑制支持这些预测。结果表明，奎纳克林通过靶向核糖体生物合成治疗急性髓系白血病具有重新定位的潜力。
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.
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影响因子：
3
作者：
Haglund, Caroline;Aleskog, Anna;Lindhagen, Elin
通讯作者：
Lindhagen, Elin
影响因子：
2.7
作者：
Falantes, Jose F.;Trujillo, Pablo;Perez-Simon, Jose A.
通讯作者：
Perez-Simon, Jose A.
DOI：
10.1186/1478-811x-9-13
发表时间：
2011-05-15
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Ehsanian R;Van Waes C;Feller SM
通讯作者：
Feller SM
影响因子：
2.1
作者：
Cree, Ian A.
通讯作者：
Cree, Ian A.
影响因子：
4.8
作者：
Jani, Tanvi S.;DeVecchio, Jennifer;Houghton, Janet A.
通讯作者：
Houghton, Janet A.