Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.
Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.
McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
Eleftherios
E
Sachlos
Ruth M
RM
Risueño
Sarah
S
Laronde
Zoya
Z
Shapovalova
Jong-Hee
JH
Lee
Jennifer
J
Russell
Monika
M
Malig
Jamie D
JD
McNicol
Aline
A
Fiebig-Comyn
Monica
M
Graham
Marilyne
M
Levadoux-Martin
Jung Bok
JB
Lee
Andrew O
AO
Giacomelli
John A
JA
Hassell
Daniela
D
Fischer-Russell
Michael R
MR
Trus
Ronan
R
Foley
Brian
B
Leber
Anargyros
A
Xenocostas
Eric D
ED
Brown
Tony J
TJ
Collins
Mickie
M
Bhatia
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology; D015767:Mefloquine / Q000494:pharmacology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D039904:Pluripotent Stem Cells / Q000187:drug effects; D011714:Pyrans / Q000494:pharmacology; D013881:Thioridazine / Q000494:pharmacology*; D000095662:Polyether Polyketides
D000970:Antineoplastic Agents; D003561:Cytarabine; D018492:Dopamine Antagonists; D015767:Mefloquine; D011714:Pyrans; D013881:Thioridazine; C010327:salinomycin; D000095662:Polyether Polyketides