Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. Oncotarget 2016 Feb 09;7(6):7268-79
Date
01/16/2016Pubmed ID
26771236Pubmed Central ID
PMC4872784DOI
10.18632/oncotarget.6896Scopus ID
2-s2.0-84980701332 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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.
Author List
Fox JM, Moynihan JR, Mott BT, Mazzone JR, Anders NM, Brown PA, Rudek MA, Liu JO, Arav-Boger R, Posner GH, Civin CI, Chen XAuthor
Ravit Boger MD Chief, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntimalarials
Antineoplastic Agents
Apoptosis
Artemisinins
Blotting, Western
Cell Proliferation
Drug Synergism
Drug Therapy, Combination
Humans
Immunoenzyme Techniques
Leukemia, Myeloid, Acute
Male
Mice
Mice, Inbred NOD
Mice, SCID
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Reactive Oxygen Species
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
