title: Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs.
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.
authors.affiliation: Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Moynihan
authors.affiliation: Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.affiliation: Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Mazzone
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Anders
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Brown
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
authors.forename: Ravit
authors.initials: R
authors.lastname: Arav-Boger
authors.affiliation: Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.|Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
authors.affiliation: Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Curt I
authors.initials: CI
authors.lastname: Civin
authors.affiliation: Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D017382:Reactive Oxygen Species
keywords: ART-838; ROS; artemisinins; chemotherapy; leukemia