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Acute Myeloid Leukemia
Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells
Haematologica 2018 Volume 103(9):1472-1483
1Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, China; 2CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), China; 3Guangdong Institute for Drug Control, Guangzhou, China; 4Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, China; 5Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, MD, USA; 6Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel; 7Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA; 8Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 9Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, OH, USA and 10Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, OH, USA
Dang Wu,1,# Wanyan Wang,1,# Wuyan Chen,2 Fulin Lian,2 Li Lang,1 Ying Huang,3 Yechun Xu,2 Naixia Zhang,2 Yinbin Chen,4 Mingyao Liu,4 Ruth Nussinov,5,6 Feixiong Cheng,7,8,9,10 Weiqiang Lu4 and Jin Huang1
#DW and WW contributed equally to this work.
ABSTRACT
Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that over- come myeloid differentiation have been shown to be a promising thera- peutic 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 differ- entiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydrooro- tate dehydrogenase inhibitor, isobavachalcone, derived from the tradi- tional Chinese medicine Psoralea corylifolia. Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isother- mal titration calorimetry experiments, we demonstrate that isobavachal- cone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HL60 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 dif- ferentiation of acute myeloid leukemia cells via pharmacological inhibi- tion of human dihydroorotate dehydrogenase, offering a potential thera- peutic strategy for acute myeloid leukemia.
Introduction
Acute myeloid leukemia (AML) is a malignant disorder characterized by differ- entiation and abnormal growth of hematopoietic stem or progenitor cells.1 AML is typically associated with a rapid onset of symptoms attributed to bone marrow
Correspondence:
huangjin@ecust.edu.cn or wqlu@bio.ecnu.edu.cn or chengf@ccf.org
Received: January 10, 2018. Accepted: May 30, 2018. Pre-published: June 7, 2018.
doi:10.3324/haematol.2018.188185
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/9/1472
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