Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood 2009 Oct 01;114(14):3064-73
Date
07/11/2009Pubmed ID
19589922DOI
10.1182/blood-2009-03-209965Scopus ID
2-s2.0-70449466605 (requires institutional sign-in at Scopus site) 158 CitationsAbstract
Off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted 2 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 with control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in nonobese diabetic/severe combined immunodeficiency 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 anticancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies, including leukemia and myeloma.
Author List
Eberhard Y, McDermott SP, Wang X, Gronda M, Venugopal A, Wood TE, Hurren R, Datti A, Batey RA, Wrana J, Antholine WE, Dick JE, Schimmer ADMESH terms used to index this publication - Major topics in bold
AnimalsAntifungal Agents
Antimetabolites, Antineoplastic
Apoptosis
Cells, Cultured
Cytarabine
Drug Synergism
Electron Spin Resonance Spectroscopy
Fibroblasts
Humans
Immunoblotting
Inhibitor of Apoptosis Proteins
Iron
Iron Chelating Agents
Leukemia, Myeloid, Acute
Luciferases
Lung
Mice
Mice, Inbred NOD
Mice, SCID
Microtubule-Associated Proteins
Multiple Myeloma
Promoter Regions, Genetic
Pyridones
Ribonucleotide Reductases
