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Blood, 1 October 2009, Vol. 114, No. 14, pp. 3064-3073. Prepublished online as a Blood First Edition Paper on July 9, 2009; DOI 10.1182/blood-2009-03-209965. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-03-209965v1 114/14/3064    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Eberhard, Y. Articles by Schimmer, A. D. PubMed PubMed Citation Articles by Eberhard, Y. Articles by Schimmer, A. D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 10, 2009 Accepted June 25, 2009 Chelation of intracellular iron with the anti-fungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells Yanina Eberhard, Sean McDermott, Xiaoming Wang, Marcela Gronda, Amudha Venugopal, Tabitha E. Wood, Rose Hurren, Alessandro Datti, Robert A. Batey, Jeffrey Wrana, William E. Antholine, John Dick, and Aaron D. Schimmer* The Princess Margaret Hospital, The Ontario Cancer Institute, Toronto, ON, Canada Toronto General Research Institute, University Health Network, Toronto, ON, Canada Department of Chemistry, University of Toronto, Toronto, ON, Canada Mount Sinai Hospital, Toronto, ON, Canada National Biomedical EPR Center, Medical College of Wisconsin, Milwaukee, WI, United States Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada * Corresponding author; email: aaron.schimmer{at}utoronto.ca. Off-patent drugs with previously unrecognized anti-cancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted two independent cell-based chemical screens and identified the antimicrobial, ciclopirox olamine (CPX) in both screens. CPX decreased cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared to control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in NOD/SCID mouse models, thereby establishing its ability to target leukemia stem cells. Mechanistically, CPX bound intracellular iron and this intracellular iron chelation was functionally important for its cytotoxicity. By electron paramagnetic resonance, CPX inhibited the iron-dependent enzyme ribonucleotide reductase at concentrations associated with cell death. Thus, in summary, CPX has previously unrecognized anti-cancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies including leukemia and myeloma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Screens, iron, and leukemia Richard M. Stone and Daniel J. DeAngelo Blood 2009 114: 2857-2858. [Full Text] [PDF] This article has been cited by other articles: R. M. Stone and D. J. DeAngelo Screens, iron, and leukemia Blood, October 1, 2009; 114(14): 2857 - 2858. [Full Text] [PDF]

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