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

Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive haematopoietic stem cells. Intervention that overcomes myeloid differentiation has been shown a promising therapeutic strategy for acute myeloid leukemia. In this study, we show 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 identify a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from 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 directly inhibits human dihydroorotate dehydrogenase, 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 isobavachalcone and adriamycin combination prolong survival in an intravenous HL60 leukemia model. Collectively, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute myeloid leukemia cells via pharmacologic inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia. Copyright © 2018, Ferrata Storti Foundation.

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