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<p>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.</p>

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A novel strategy to target metabolic dependencies in acute myeloid leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月4日

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  • Nithya Balasundaram,
  • Hamenth Kumar Palani,
  • Arvind Venkatraman,
  • Yolanda Augustin,
  • Shruthi Pichandi,
  • Clement Regnault,
  • Majeela Solomon,
  • Abirami Rajasekaran,
  • Mohammed Yasar,
  • Swathy Palani Kumar,
  • Reeshma Nair Radhakrishnan,
  • Anu Korula,
  • Uday Prakash Kulkarni,
  • Eunice Sindhuvi Edison,
  • Poonkuzhali Balasubramanian,
  • Biju George,
  • Aby Abraham,
  • Sanjeev Krishna,
  • Vikram Mathews

摘要

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.