Inhibition of pyrimidine biosynthesis by strobilurin derivatives induces differentiation of acute myeloid leukemia cells

Abstract

All-trans retinoic acid–based differentiation therapies have succeeded in the treatment of acute promyelocytic leukemia, which is a rare subtype of acute myeloid leukemia (AML). Their clinical efficacy is negligible, however, for other subtypes of AML. Here, we showed that strobilurin derivatives, a well-established class of inhibitors of mitochondrial electron transport chain (ETC) complex III, possessed differentiation-inducing activity in AML cells. Impairment of mitochondrial ETC activity was involved in the differentiation effects of strobilurin derivatives, where reactive oxygen species generation appeared unnecessary. Conversely, strobilurin derivative-mediated differentiation was triggered by pyrimidine deficiency, which resulted from the inhibition of the mitochondrial-coupled dihydroorotate dehydrogenase enzyme. Moreover, strobilurin derivative-mediated pyrimidine depletion led to the activation of the Akt/mTOR cascade, which was required for the differentiation. Our study provided evidence that strobilurin derivatives may represent a novel class of differentiation-inducing agents for the treatment of AML.

Keywords:

• Strobilurin derivatives
• mitochondria
• pyrimidines biosynthesis
• Akt
• differentiation
• acute myeloid leukemia

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [81273544], the Scientific Research Project of the Chinese People’s Liberation Army (PLA) [AWS16J014], and the National Major Science and Technology Projects of China [2018ZX09J18103-003].