Artesunate, a new antimalarial clinical drug, exhibits potent anti-AML activity by targeting the ROS/Bim and TFRC/Fe pathways.

Background And Purpose: Artesunate, approved by the Food and Drug Administration in 2020 as a new treatment for severe malaria, also shows anti-tumour activity against acute myeloid leukaemia (AML). However, the underlying molecular mechanism(s) of artesunate-induced apoptosis and differentiation of AML is not clearly elucidated.

Experimental Approach: The biological effects of artesunate on AML were explored in vitro, using cells from AML patients and leukaemia cell lines, and in vivo, using female C57BL/6 or nude nu/nu BALB/c mice. Underlying mechanisms in vitro were examined with the Trypan blue dye exclusion assay, western blotting and flow cytometry. Effects of artesunate in C57BL/6 mice intravenously injected with murine AML cells (C1498-GFP) were assessed by numbers of AML cells and by survival.

Key Results: In vitro, artesunate promoted apoptosis and differentiation in both leukaemia cell lines and patient-derived primary leukaemia cells. Mechanistically, artesunate promoted cell apoptosis by triggering reactive oxygen species (ROS) production and increasing expression of the pro-apoptotic protein Bim. Interestingly, transferrin receptor 1 (TFRC)-mediated regulation of intracellular iron homeostasis also played an essential role in AML cell differentiation induced by artesunate. In vivo, artesunate slowed AML progression and prolonged survival in a mouse leukaemia model. Notably, artesunate displayed no apparent toxicity towards healthy haematopoietic stem cells, bone marrow mononuclear cells or experimental animals.

Conclusion And Implications: Artesunate is a safe agent with significant anti-leukaemia effects in mice and may serve as a promising chemotherapeutic strategy for patients with AML, based on two different mechanisms, targeting the ROS/Bim and the TFRC/Fe pathways.