Low-dose salinomycin induces anti-leukemic responses in AML and MLL

Roulston, Gary D.R. and Burt, Charlotte L. and Kettyle, Laura M.J. and Matchett, Kyle B. and Keenan, Heather L. and Mulgrew, Nuala M. and Ramsey, Joanne M. and Dougan, Caoifa and McKiernan, John and Grishagin, Ivan V. and Mills, Ken I. and Thompson, Alexander (2016) Low-dose salinomycin induces anti-leukemic responses in AML and MLL. Oncotarget . ISSN 1949-2553

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Abstract

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.

Item Type: Article
Keywords: drug repurposing, salinomycin, anti-leukemia, gene signature, AML/MLL-rearrangements
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine
Identification Number: 10.18632/oncotarget.11866
Depositing User: Eprints, Support
Date Deposited: 20 Oct 2016 14:30
Last Modified: 15 Oct 2017 19:35
URI: http://eprints.nottingham.ac.uk/id/eprint/37804

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