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

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

  • Haematologica. 2018 Sep;103(9):1472-1483. doi: 10.3324/haematol.2018.188185.
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 Lu 11,  Jin Huang 12
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, China.
  • 2 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), China.
  • 3 Guangdong Institute for Drug Control, Guangzhou, China.
  • 4 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, China.
  • 5 Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, MD, USA.
  • 6 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
  • 7 Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA huangjin@ecust.edu.cn wqlu@bio.ecnu.edu.cn chengf@ccf.org.
  • 8 Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 9 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, OH, USA.
  • 10 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, OH, USA.
  • 11 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, China huangjin@ecust.edu.cn wqlu@bio.ecnu.edu.cn chengf@ccf.org.
  • 12 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, China huangjin@ecust.edu.cn wqlu@bio.ecnu.edu.cn chengf@ccf.org.
PMID: 29880605 DOI: 10.3324/haematol.2018.188185
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 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 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 differentiation of acute myeloid leukemia cells via pharmacological inhibition of human Dihydroorotate Dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia.

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