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Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells

文献类型：期刊论文

作者Wu, Dang2; Wang, Wanyan2; Chen, Wuyan3; Lian, Fulin3; Lang, Li2; Huang, Ying1; Xu, Yechun3; Zhang, Naixia3; Chen, Yinbin4,5; Liu, Mingyao4,5
刊名HAEMATOLOGICA
出版日期2018-08-31
卷号103期号:9页码:1472-1483
ISSN号0390-6078
DOI10.3324/haematol.2018.188185
文献子类Article
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.
WOS关键词PYRIMIDINE SYNTHESIS ; CANCER-CELLS ; MYC ; THERAPY ; COMBINATION ; SENSITIVITY ; SUPPRESSION ; EXPRESSION ; PATHWAYS ; DISEASE
资助项目National Natural Science Foundation of China[81773775] ; Shanghai Committee of Science and Technology[15431902000] ; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University)[CMEMR2017-B01] ; National Heart, Lung, and Blood Institute of the National Institutes of Health[K99HL138272] ; Federal funds from Frederick National Laboratory for Cancer Research, National Institutes of Health[HHSN261200800001E] ; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research[00000000]
WOS研究方向Hematology
语种英语
WOS记录号WOS:000443259100022
出版者FERRATA STORTI FOUNDATION
源URL[http://119.78.100.183/handle/2S10ELR8/279607]  
专题药物发现与设计中心
分析化学研究室
通讯作者Cheng, Feixiong; Lu, Weiqiang; Huang, Jin
作者单位1.Guangdong Inst Drug Control, Guangzhou, Guangdong, Peoples R China;
2.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, 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;
推荐引用方式
GB/T 7714		 Wu, Dang,Wang, Wanyan,Chen, Wuyan,et al. Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells[J]. HAEMATOLOGICA,2018,103(9):1472-1483.
APA Wu, Dang.,Wang, Wanyan.,Chen, Wuyan.,Lian, Fulin.,Lang, Li.,...&Huang, Jin.(2018).Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells.HAEMATOLOGICA,103(9),1472-1483.
MLA Wu, Dang,et al."Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells".HAEMATOLOGICA 103.9(2018):1472-1483.

入库方式： OAI收割

来源：上海药物研究所

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