文献类型：期刊文献

英文题名：Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells

作者：Wu, Dang[1];Wang, Wanyan[1];Chen, Wuyan[2];Lian, Fulin[2];Lang, Li[1];Huang, Ying[3];Xu, Yechun[2];Zhang, Naixia[2];Chen, Yinbin[4,5];Liu, Mingyao[4,5];Nussinov, Ruth[6,7];Cheng, Feixiong[8,9,10,11,12,13];Lu, Weiqiang[4,5];Huang, Jin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China;[3]Guangdong Inst Drug Control, Guangzhou, Guangdong, Peoples R China;[4]East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai, Peoples R China;[5]East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China;[6]NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA;[7]Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, Tel Aviv, Israel;[8]Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA;[9]Northeastern Univ, Dept Phys, Boston, MA 02115 USA;[10]Harvard Med Sch, Ctr Canc Syst Biol, Boston, MA 02115 USA;[11]Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA;[12]Cleveland Clin, Lerner Res Inst, Genom Med Inst, Cleveland, OH 44106 USA;[13]Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Mol Med, Cleveland, OH 44106 USA

年份：2018

卷号：103

期号：9

起止页码：1472

外文期刊名：HAEMATOLOGICA

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000443259100022)】；

基金：Funds: this work was supported by the National Natural Science Foundation of China (81773775), Shanghai Committee of Science and Technology (15431902000), and State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University, CMEMR2017-B01). This work was also supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K99HL138272 to FC. The project was funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was also supported [in part] by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

语种：英文

摘要：Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived om primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine Psoralea corylifolia. Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isothermal titration calorimetry experiments, we demonstrate that isobavachalcone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HMO xenograft tumor growth without obvious toxicity. Importantly, our results suggest that a combination of isobavachalcone and adriamycin prolonged survival in an intravenous HL60 leukemia model. In summary, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute myeloid leukemia cells via pharmacological inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia.