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Introduction
Ivermectin, a polycyclic lactone pesticide produced by bacterium Streptomyces avermitilis is a broad-spectrum antiparasitic drug that has been used in human medicine since 1987 (1). It is the drug of choice in treating onchocerciasis and strongyloidiasis, and as a therapeutic option for mass population treatment campaigns for lymphatic filariasis. As a microfilaricide, a single dose of ivermectin is fast, effective and well tolerated, and causes little to no severe inflammatory responses (2). Commonly observed adverse effects from treatment with ivermectin are mild and self-limiting and include: Skin reactions (such as itching), musculoskeletal pain, fever, swelling of the face, joints and limbs, headaches and dizziness, lymphadenopathy, eye reactions and pain from parasitic nodules (3).
Previous studies on the molecular pathogenesis of cancer has improved our knowledge and increased interest in repurposing non-cancer drugs to be used against this disease (4). A study from 1996 reported that ivermectin treatment in murine multidrug-resistant (MDR)-P388 and human MDR-CEM leukemia cells was a substrate and inhibitor of P-glycoprotein-mediated multidrug resistance in cancer (5). Another study demonstrated that ivermectin, at doses of 3–5 mg/kg, was able to suppress the growth of human melanoma and a number of other cancer xenografts in mice without adverse effects (6). In 2009, a high-throughput screen was performed to identify the selective inhibitors of cancer stem-like cells (CSCs) and demonstrated that salinomycin treatment reduced the proportion of CSCs by >100-fold relative to paclitaxel, inhibited mammary tumor growth in vivo and increased epithelial differentiation of tumor cells, accompanied by a loss of expression of breast CSC genes (7). As salinomycin is an antiparasitic drug for veterinary use only, similar compounds for human use were investigated that may also act as selective inhibitors of CSC. The results of the present study demonstrated that ivermectin exhibits a high degree of similarity with salinomycin and preferentially inhibited the CSC subpopulation in a breast cancer model.
Materials and methods
Computational searches
To systematically identify FDA approved drugs that exhibit similar activity as salinomycin, a fast computational search of the DrugBank database 4.0 of approved drugs was performed (8). Using the principles of similarity searching with two-dimensional fingerprints, the chemical structure of salinomycin was used as a query to compute the similarity of each of 1,623 compounds in DrugBank using the...