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

• Published in: Haematologica (Roma) 2018-09, Vol.103 (9), p.1472-1483
• Main Authors: Wu, Dang, Wang, Wanyan, Chen, Wuyan, Lian, Fulin, Lang, Li, Huang, Ying, Xu, Yechun, Zhang, Naixia, Chen, Yinbin, Liu, Mingyao, Nussinov, Ruth, Cheng, Feixiong, Lu, Weiqiang, Huang, Jin
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Biomarkers, Tumor; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Chalcones - chemistry; Chalcones - pharmacology; Dihydroorotate Dehydrogenase; Disease Models, Animal; Drug Synergism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Gene Expression; Gene Knockdown Techniques; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Mice; Models, Molecular; Molecular Structure; Neoplastic Stem Cells - metabolism; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors - genetics; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Prognosis; RNA Interference; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2018.188185

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 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.