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Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells.
- Source :
-
Haematologica [Haematologica] 2018 Sep; Vol. 103 (9), pp. 1472-1483. Date of Electronic Publication: 2018 Jun 07. - Publication Year :
- 2018
-
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.<br /> (Copyright© 2018 Ferrata Storti Foundation.)
- Subjects :
- Animals
Apoptosis genetics
Biomarkers, Tumor
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
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 genetics
Oxidoreductases Acting on CH-CH Group Donors metabolism
Prognosis
RNA Interference
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Apoptosis drug effects
Cell Differentiation drug effects
Enzyme Inhibitors pharmacology
Oxidoreductases Acting on CH-CH Group Donors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 103
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 29880605
- Full Text :
- https://doi.org/10.3324/haematol.2018.188185