Abstract
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.
Highlights
Artemisinin, a natural antimalarial compound, is the active component of the sweet wormwood plant (Artemisia annua L.) used in traditional Chinese medicine to treat fevers [1]
First-generation artemisinin derivatives such as AS have enhanced antimalarial and antineoplastic www.impactjournals.com/oncotarget activity compared to natural artemisinin, they are rapidly catabolized in vivo to the active metabolite dihydroartemisinin (DHA), which is glucuronidated and excreted [16]
In our recent structureactivity relationship study of artemisinin trioxane dimers, we identified artemisininderived trioxane diphenylphosphate dimer 838 (ART-838) as an exquisitely potent antileukemic drug, with a nearly 70-fold lower IC50 than that of AS against Jurkat T-cell acute lymphoblastic leukemia (T-ALL) cells [22]
Summary
Artemisinin, a natural antimalarial compound, is the active component of the sweet wormwood plant (Artemisia annua L.) used in traditional Chinese medicine to treat fevers [1]. Artemisinins inhibit growth of a broad range of microbes and cancer cells, especially leukemias [2,3,4]. Artemisinins appear to inhibit cancers by mechanisms that differ from those of established antineoplastic agents, and chemotherapyresistant leukemia and neuroblastoma cell lines remain sensitive to artemisinins [2, 5, 6]. In our recent structureactivity relationship study of artemisinin trioxane dimers, we identified ART-838 as an exquisitely potent antileukemic drug, with a nearly 70-fold lower IC50 than that of AS against Jurkat T-cell acute lymphoblastic leukemia (T-ALL) cells [22]. We demonstrated a favorable therapeutic window for ART-838, wherein it inhibited growth of leukemia cells but not normal peripheral blood mononuclear cells, similar to results of ART-838 in solid tumor cell lines compared to normal fibroblasts [11]
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