Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs
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Jennifer M. Fox1, James R. Moynihan1, Bryan T. Mott2, Jennifer R. Mazzone2, Nicole M. Anders3, Patrick A. Brown3, Michelle A. Rudek3, Jun O. Liu4, Ravit Arav-Boger5, Gary H. Posner2,6, Curt I. Civin1,*, Xiaochun Chen1,*
1Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
2Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA
3Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
4Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
5Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
6Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, Baltimore, MD 21205, USA
*These authors have contributed equally to this work
Xiaochun Chen, e-mail: [email protected]
Curt I. Civin, e-mail: [email protected]
Keywords: artemisinins, ART-838, leukemia, ROS, chemotherapy
Received: September 17, 2015 Accepted: January 06, 2016 Published: January 12, 2016
Artemisinins, endoperoxide-containing molecules, best known as antimalarials, have potent antineoplastic activity. The established antimalarial, artesunate (AS), and the novel artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838) inhibited growth of all 23 tested acute leukemia cell lines, reduced cell proliferation and clonogenicity, induced apoptosis, and increased intracellular levels of reactive oxygen species (ROS). ART-838 was 88-fold more potent that AS in vitro, inhibiting all leukemia cell lines at submicromolar concentrations. Both ART-838 and AS cooperated with several established antileukemic drugs and newer kinase inhibitors to inhibit leukemia cell growth. ART-838 had a longer plasma half-life than AS in immunodeficient NOD-SCID-IL2Rgnull (NSG) mice, remaining at effective antileukemic concentrations for >8h. Intermittent cycles of ART-838 inhibited growth of acute leukemia xenografts and primagrafts in NSG mice, at higher potency than AS. Based on these preclinical data, we propose that AS, with its established low toxicity and low cost, and ART-838, with its higher potency and longer persistence in vivo, should be further developed toward integration into antileukemic regimens.
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