Targeting Metabolic Dependencies in Acute Myeloid Leukemia: A Dual Strategy using Arsenic Trioxide and Artesunate.

Balasundaram, N.; Venkatraman, A.; Augustin, Y.; Palani, H. K.; Regnault, C.; Korula, A.; Kulkarni, U. P.; Edison, E. S.; Balasubramanian, P.; George, B.; Abraham, A.; Krishna, S.; Mathews, V.

doi:10.1101/2024.06.23.600168

bioRxiv · 10.1101/2024.06.23.600168

Targeting Metabolic Dependencies in Acute Myeloid Leukemia: A Dual Strategy using Arsenic Trioxide and Artesunate.

Balasundaram, N.·Venkatraman, A.·Augustin, Y.·Palani, H. K.·Regnault, C.·Korula, A.·Kulkarni, U. P.·Edison, E. S.·Balasubramanian, P.·George, B.·Abraham, A.·Krishna, S.·Mathews, V.

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Abstract

Acute myeloid leukemia (AML) remains a difficult disease to cure despite recent advances. Off-target side effects of therapy, especially prolonged cytopenia, lead to significant morbidity and mortality. There is an increased recognition that in AML, there is a potentially vulnerable dependence on OXPHOS metabolism, more so in the leukemia stem cell compartment (AML-LSC) that could be exploited. Drug re-purposing screens have suggested the possible role of artesunate (ART) in inhibiting mitochondrial respiration and arsenic trioxide (ATO) in inhibiting glycolysis. Here, we explore the potential of using a combination of ART and ATO to treat AML. Through in-vitro and in-vivo studies, we demonstrate the potential of this combination along with hypo-methylating agents and other mitocans, such as BCL-2 inhibitor venetoclax, to be used in the treatment of AML with minimal off-target effect on normal hematopoietic stem cells (HSC). These observations warrant further exploration of such novel combinations in clinical trials.

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Balasundaram, N., Venkatraman, A., Augustin, Y., Palani, H. K., Regnault, C., Korula, A., Kulkarni, U. P., Edison, E. S., Balasubramanian, P., George, B., Abraham, A., Krishna, S., Mathews, V.. 2024-06-28. Targeting Metabolic Dependencies in Acute Myeloid Leukemia: A Dual Strategy using Arsenic Trioxide and Artesunate.. https://doi.org/10.1101/2024.06.23.600168

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