The off-Patent Anti-Fungal Ciclopirox Olamine Displays Preclinical Activity in Leukemia and Myeloma

• Published in: Blood 2008-11, Vol.112 (11), p.944-944
• Main Authors: Eberhard, Yanina, Venugopal, Amudha, Gronda, Marcela, Hurren, Rose, Datti, Alessandro, Wrana, Jeff, Antholine, William E, Schimmer, Aaron D.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V112.11.944.944

Off-patent drugs with previously unrecognized anti-cancer activity could be rapidly repurposed for this new indication given their prior testing for safety and toxicity. To identify such compounds, we developed, automated and conducted a cell-based chemical screen of 4800 off-patent drugs and chemicals. From this chemical screen, we identified the off-patent antimicrobial, ciclopirox olamine (CPX) that is currently used for the topical treatment of cutaneous fungal infections, but has not been previously evaluated as a systemic agent for the treatment of malignancy. As an anti-fungal agent, the mechanism of action of CPX is not well understood, but appears related to binding intracellular iron and inhibiting iron containing enzymes. To explore its efficacy and mechanism of action as an anticancer agent, leukemia, myeloma, and solid tumor cell lines were treated with increasing concentrations of CPX. 72 hours after incubation, cell viability was measured by the MTS assay. CPX decreased cell viability in 5/9 leukemia, 3/6 myeloma, and 3/5 solid tumor cells with an LD50 < 5 uM, a concentration that is pharmacologically achievable based on prior animal studies investigating CPX as an anti-fungal. Cell death was confirmed by the presence of a subG1 peak by flow cytometry after staining cells with propidium iodide. In contrast, CPX was less toxic to MRC 5, LF1, and GMO 5757 non malignant fibroblasts with an LD50 > 20 uM. Next, we evaluated CPX in combination with cytarabine and daunorubicin, standard chemotherapeutic agents used in the treatment of AML. In AML cell lines, CPX synergistically enhanced the cytotoxicity of cytarabine as determined by the median effect isobologram analysis. Specifically, the combination indices (CI) at the EC50, 75 and 90 were 0.18, 0.19, and 0.24, respectively, where a CI < 1 denotes synergy. In contrast, the addition of CPX to daunorubicin produced only additive effects. Given the effects in leukemia cells lines, we evaluated the effects of oral CPX in 3 mouse models of leukemia. Sublethally irradiated NOD-SCID mice were injected subcutaneously with OCI-AML2 or K562 human leukemia cells or intraperitoneally with MDAY-D2 murine leukemia cells. After tumor implantation, mice were treated with CPX (25mg/kg) in water or water alone by oral gavage. Oral CPX decreased tumor weight and volume in all 3 mouse models by up to 65% compared to control without evidence of weight loss or gross organ toxicity. Mechanistically, CPX arrested cells