Low-dose salinomycin induces anti-leukemic responses in AML and MLL.
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.
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Gary D R
GD
Roulston
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Charlotte L
CL
Burt
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Laura M J
LM
Kettyle
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Kyle B
KB
Matchett
Cambridge University School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, CB2 0SP, United Kingdom.
Heather L
HL
Keenan
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Nuala M
NM
Mulgrew
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Joanne M
JM
Ramsey
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Caoifa
C
Dougan
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
John
J
McKiernan
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Ivan V
IV
Grishagin
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.
Ken I
KI
Mills
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, United Kingdom.|Division of Cancer and Stem Cells, School of Medicine, Wolfson Centre for Stem Cells, Tissue Engineering & Modelling (STEM), University of Nottingham, Nottingham, NG7 2RD, United Kingdom.
Alexander
A
Thompson
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D011714:Pyrans / Q000008:administration & dosage*; D000095662:Polyether Polyketides
D000970:Antineoplastic Agents; D011495:Histone-Lysine N-Methyltransferase; D051788:Myeloid-Lymphoid Leukemia Protein; D011714:Pyrans; C497422:KMT2A protein, human; C010327:salinomycin; D000095662:Polyether Polyketides
AML/MLL-rearrangements; anti-leukemia; drug repurposing; gene signature; salinomycin