Author/Authors :
Eleftherios Sachlos، نويسنده , , Ruth M. Risue?o، نويسنده , , Sarah Laronde، نويسنده , , Zoya Shapovalova، نويسنده , , Jong-Hee Lee، نويسنده , , Jennifer Russell، نويسنده , , Monika Malig، نويسنده , , Jamie D. McNicol، نويسنده , , Aline Fiebig-Comyn، نويسنده , , Monica Graham، نويسنده , , Marilyne Levadoux-Martin، نويسنده , , Jung Bok Lee، نويسنده , , Andrew O. Giacomelli، نويسنده , , John A. Hassell، نويسنده , , Daniela Fischer-Russell، نويسنده , , Michael R. Trus، نويسنده , , Ronan Foley، نويسنده , , Brian Leber، نويسنده , , Anargyros Xenocostas، نويسنده , , Eric D. Brown، نويسنده , , et al.، نويسنده ,
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.
