期刊
HAEMATOLOGICA
卷 103, 期 9, 页码 1472-1483出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.188185
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资金
- 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
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.
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