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

Gary DR Roulston, Charlotte L Burt, Laura MJ Kettyle, Kyle B Matchett, Heather L Keenan, Nuala M Mulgrew, Joanne M Ramsey, Caoifa Dougan, John McKiernan, Ivan V Grishagin, Ken I Mills, Alexander Thompson

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.
LanguageEnglish
Pages73448-73461
Number of pages14
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 1 Sep 2016

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Coccidiostats
Ionophores
salinomycin
Computational Biology
Transducers
Pharmaceutical Preparations
Genes
Neoplasms
Leukemia
Proteins
Therapeutics
Transplantation
Clinical Trials
Breast Neoplasms
Cell Line
Survival

Cite this

Roulston, G. DR., Burt, C. L., Kettyle, L. MJ., Matchett, K. B., Keenan, H. L., Mulgrew, N. M., ... Thompson, A. (2016). Low-dose salinomycin induces anti-leukemic responses in AML and MLL. 7(45), 73448-73461. https://doi.org/10.18632/oncotarget.11866
Roulston, Gary DR ; Burt, Charlotte L ; Kettyle, Laura MJ ; Matchett, Kyle B ; Keenan, Heather L ; Mulgrew, Nuala M ; Ramsey, Joanne M ; Dougan, Caoifa ; McKiernan, John ; Grishagin, Ivan V ; Mills, Ken I ; Thompson, Alexander. / Low-dose salinomycin induces anti-leukemic responses in AML and MLL. 2016 ; Vol. 7, No. 45. pp. 73448-73461.
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Roulston, GDR, Burt, CL, Kettyle, LMJ, Matchett, KB, Keenan, HL, Mulgrew, NM, Ramsey, JM, Dougan, C, McKiernan, J, Grishagin, IV, Mills, KI & Thompson, A 2016, 'Low-dose salinomycin induces anti-leukemic responses in AML and MLL', vol. 7, no. 45, pp. 73448-73461. https://doi.org/10.18632/oncotarget.11866

Low-dose salinomycin induces anti-leukemic responses in AML and MLL. / Roulston, Gary DR; Burt, Charlotte L; Kettyle, Laura MJ; Matchett, Kyle B; Keenan, Heather L; Mulgrew, Nuala M; Ramsey, Joanne M; Dougan, Caoifa; McKiernan, John; Grishagin, Ivan V; Mills, Ken I; Thompson, Alexander.

Vol. 7, No. 45, 01.09.2016, p. 73448-73461.

Research output: Contribution to journalArticle

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AU - Roulston, Gary DR

AU - Burt, Charlotte L

AU - Kettyle, Laura MJ

AU - Matchett, Kyle B

AU - Keenan, Heather L

AU - Mulgrew, Nuala M

AU - Ramsey, Joanne M

AU - Dougan, Caoifa

AU - McKiernan, John

AU - Grishagin, Ivan V

AU - Mills, Ken I

AU - Thompson, Alexander

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Y1 - 2016/9/1

N2 - 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.

AB - 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.

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DO - https://doi.org/10.18632/oncotarget.11866

M3 - Article

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Roulston GDR, Burt CL, Kettyle LMJ, Matchett KB, Keenan HL, Mulgrew NM et al. Low-dose salinomycin induces anti-leukemic responses in AML and MLL. 2016 Sep 1;7(45):73448-73461. https://doi.org/10.18632/oncotarget.11866