FDA-approved drugs with previously unrecognized anti-cancer activity could be rapidly repurposed for this new indication. We compiled a library of such off-patent drugs to screen four leukemia cell lines and identified the anti-parasitic agent ivermectin that induced cell death at low micromolar concentrations. In cell death and clonogenic growth assays, low micromolar concentration of ivermectin significantly reduced viability of leukemia cell lines and patient samples compared to normal peripheral blood stem cells. In xenograft mouse models of leukemia, ivermectin decreased tumor volume and weight by up to 72% when compared to control without observable toxicity at pharmacologically achievable dosage. In this study, we further demonstrate that ivermectin activates chloride channels in leukemia cells leading to membrane hyperpolarization and increased reactive oxygen species generation. In addition, it demonstrated synergistic interaction when used in combination with Daunorubicin and Cytarabine. Therefore, this study highlights a potential new therapeutic strategy in repurposing ivermectin for the treatment of AML.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/24641 |
| Date | 28 July 2010 |
| Creators | Sharmeen, Sumaiya |
| Contributors | Schimmer, Aaron D. |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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