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Editorials
Figure 1. Isobavachalcone in the regulation of dihydroorotate dehydrogenase in pyrimidine biosynthesis and myeloid blast differentiation. Left, the pyrimidine biosynthesis pathway and its biological functions. Isobavachalcone (IBC) prevents DHODH from catalyzing dihydroorotate into orotate, blocking pyrimidine biosynthe- sis, resulting in myeloid lineage differentiation and induction of apoptosis. The role of DHODH and the negative impact of c-MYC on myeloid blast differentiation is indicated by the dotted line/arrow. DHODH: dihydroorotate dehydrogenase; UMP: uridine 5′-monophosphate; UTP: uridine triphosphate; CTP: cytidine triphosphate; dTTP: deoxythymidine triphosphate; UDP-GlcNAc: uridine diphosphate N-acetylglucosamine; CDP-DAG: cytidine diphosphate diacylglycerol; CDP-choline: cytidine diphosphate choline; O-GlcNAc: O-linked N-acetylglucosamine; OGT: O-GlcNAc transferase. CTP to dTTP requires multiple steps.
interplay between DHODH and c-MYC in AML triggers differentiation and whether this is dependent on cellular context, is worthy of future exploration. Importantly, the capacity of isobavachalcone to facilitate blast differentia- tion in patient-derived xenografts and AML patients with different cytogenetic abnormalities needs to be addressed. In studies similar to that of Wu and Wong et al., two groups recently reported new findings related to anti-leukemia mechanisms of DHODH inhibition in dif- ferent types of hematologic malignancies. DHODH blockade by the chiral tetrahydroindazole ([R]-HZ00), a newly developed DHODH inhibitor, increased p53 acti- vation and enhanced the anti-leukemic effect of the MDM2 inhibitor, Nutlin3a, in p53-WT chronic myeloid leukemia.19 PTC299, identified as a VEGFA inhibitor, tar- geted DHODH, resulting in cell growth inhibition and differentiation in leukemias, including AML, linking DHODH regulation and stress-induced VEGFA and angiogenesis.20 Notably, these studies demonstrated that DHODH inhibition alone is not sufficient to eliminate leukemia, requiring combination with standard chemotherapeutic agents or target-specific inhibitors. Given the genetic complexity of AML, future use of DHODH inhibitors in combination with selected drugs
with non-overlapping mechanisms of action may tackle specific aspects of the complex pathogenesis of AML and ultimately improve patients’ outcomes.
References
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