Oncotarget

Research Papers:

Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs

Jennifer M. Fox, James R. Moynihan, Bryan T. Mott, Jennifer R. Mazzone, Nicole M. Anders, Patrick A. Brown, Michelle A. Rudek, Jun O. Liu, Ravit Arav-Boger, Gary H. Posner, Curt I. Civin and Xiaochun Chen _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:7268-7279. https://doi.org/10.18632/oncotarget.6896

Metrics: PDF 1336 views  |   HTML 1680 views  |   ?  


Abstract

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

Correspondence to:

Xiaochun Chen, e-mail: xiachen@som.umaryland.edu

Curt I. Civin, e-mail: ccivin@som.umaryland.edu

Keywords: artemisinins, ART-838, leukemia, ROS, chemotherapy

Received: September 17, 2015    Accepted: January 06, 2016    Published: January 12, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 6896