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

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.

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

“…Given the role of O-GlcNAc in posttranslational modifications [47] and in chondrogenic, osteogenic and adipogenic differentiation [48][49][50][51], it is certainly plausible that O-GlcNAcylation also plays a role in myeloid differentiation. Interestingly, DHODH-induced reduction of O-GlcNAc was recently postulated to reduce c-Myc stability and thereby promote induction of differentiation [52].…”

ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia

“…27 Isobavachalcone, a natural product, has been reported to target DHODH, resulting in apoptosis and differentiation of AML cell lines at high concentration (10 µM) in vitro. 28 A novel DHODH inhibitor, BAY 2402234, induces differentiation and proliferation inhibition in multiple AML subtypes and is currently evaluated in phase I trial in myeloid malignancies. 29 In this study, we comprehensively characterise ASLAN003, a novel, potent DHODH Consistently, our RNA-seq data revealed a large family of genes associated with protein translation initiation was the top and the largest class downregulated by ASLAN003 treatment.…”

“… 27 Isobavachalcone, a natural product, has been reported to target DHODH, resulting in apoptosis and differentiation of AML cell lines at a high concentration (10 μM) in vitro . 28 BAY 2402234, a novel DHODH inhibitor, induces differentiation and inhibits proliferation in multiple AML subtypes and is currently being evaluated in a phase I trial in myeloid malignancies. 29 …”

Network Pharmacology-Based Strategy for Predicting Therapy Targets of Tripterygium wilfordii on Acute Myeloid Leukemia

“…Some traditional Chinese medicines have been proven to have a therapeutic effect on AML, such as arsenic trioxide (7) . And some other experiments also prove that traditional Chinese medicine has a therapeutic effect on AML (8) . Tripterygium wilfordii (TW), as one of the traditional Chinese medicines, there is evidence to show that the traditional Chinese medicines have anti-tumor ability (9) .…”