Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.

Eleftherios Sachlos, Ruth M Risueño, Sarah Laronde, Zoya Shapovalova, Jong-Hee Lee, Jennifer Russell, Monika Malig, Jamie D McNicol, Aline Fiebig-Comyn, Monica Graham, Marilyne Levadoux-Martin, Jung Bok Lee, Andrew O Giacomelli, John A Hassell, Daniela Fischer-Russell, Michael R Trus, Ronan Foley, Brian Leber, Anargyros Xenocostas, Eric D Brown, Tony J Collins, Mickie Bhatia

Index: Cell 149(6) , 1284-97, (2012)

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Abstract

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.Copyright © 2012 Elsevier Inc. All rights reserved.