Development of anti-
cancer drugs towards clinical application is costly and inefficient. Large screens of drugs, efficacious for non-
cancer disease, are currently being used to identify candidates for repurposing based on their anti-
cancer properties. Here, we show that low-dose
salinomycin, a coccidiostat
ionophore previously identified in a
breast cancer screen, has anti-leukemic efficacy. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar
salinomycin. Most strikingly, colony formation of normal hematopoietic cells was unaffected by
salinomycin, demonstrating a lack of hemotoxicity at the effective concentrations. Furthermore,
salinomycin treatment of primary cells resulted in loss of
leukemia repopulation ability following
transplantation, as demonstrated by extended recipient survival compared to controls. Bioinformatic analysis of a 17-gene signature identified and validated in primary MLLr cells, uncovered immunomodulatory pathways, hubs and
protein interactions as potential transducers of low dose
salinomycin treatment. Additionally, increased
protein expression of p62/Sqstm1, encoded for by one of the 17 signature genes, demonstrates a role for
salinomycin in aggresome/vesicle formation indicative of an autophagic response.Together, the data support the efficacy of
salinomycin as an anti-leukemic at non-hemotoxic concentrations. Further investigation alone or in combination with other
therapies is warranted for future clinical trial.