A novel strategy to target metabolic dependencies in acute myeloid leukemia
Acute myeloid leukemia (AML) remains difficult to cure despite recent advances. Off-target side effects of drugs currently used lead to significant morbidity and mortality. There is recognition that in AML, there is an increased dependence on OXPHOS metabolism, especially in the leukemia stem cell compartment (AML-LSC). It is also recognized that there is potential to exploit this vulnerability to treat AML. Drug re-purposing screens have suggested the potential use of artesunate (ART) to inhibit mitochondrial respiration. We have explored the potential role of ART as an additive agent in treating AML in combination with conventional therapy. Through in-vitro and in-vivo mouse model studies, we demonstrate the mechanism and efficacy of these combinations and their potential to overcome venetoclax resistance. We further demonstrate the specificity of these combinations with minimal off-target effects on normal hematopoietic stem cells (HSC). These observations warrant exploration of the additive role of ART in clinical trials.
Authors
- Radhakrishnan Rajesh (ORCID: https://orcid.org/0000-0002-9904-7946)
- Poonkuzhali Balasubramanian (ORCID: https://orcid.org/0000-0002-9443-439X)
- Hamenth Kumar Palani (ORCID: https://orcid.org/0000-0002-3404-9553)
- Eunice Sindhuvi Edison (ORCID: https://orcid.org/0000-0002-9726-1324)
- Matthew D. Solomon (ORCID: https://orcid.org/0000-0001-7846-9296)
- Aby Abraham (ORCID: https://orcid.org/0000-0002-2596-4434)
- Nithya Balasundaram (ORCID: https://orcid.org/0000-0002-0004-9483)
- Clément Regnault (ORCID: https://orcid.org/0009-0002-2702-3707)
- Anu Korula
- Arvind Venkatraman (ORCID: https://orcid.org/0000-0002-5087-1539)
- Vikram Mathews (ORCID: https://orcid.org/0000-0001-9417-2353)
- Mohammed Yasar
- Biju George (ORCID: https://orcid.org/0000-0002-9847-9501)
- Uday Kulkarni (ORCID: https://orcid.org/0000-0003-2230-2424)
- Yolanda Augustin (ORCID: https://orcid.org/0000-0001-9690-8205)
- Sanjeev Krishna (ORCID: https://orcid.org/0000-0003-0066-0634)
- Swathy Palani Kumar
- Abirami Rajasekaran
- Shruthi Pichandi
Institutions
- St George's, University of London (GB)
- Christian Medical College, Vellore (IN)
- St George’s University Hospitals NHS Foundation Trust (GB)
- Universitätsklinikum Tübingen (DE)
- Centre de Recherche Médicales de Lambaréné (GA)
- Christian Medical College (IN)
- de Duve Institute (BE)
- University of Glasgow (GB)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1038/s41419-025-08129-3
- Citations
- 2
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 3.54
Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- Anna University
- Christian Medical College, Vellore
- The Wellcome Trust DBT India Alliance
- Directorate for Biological Sciences
- National Centre for Biological Sciences