Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells | Zendy

Eleftherios Sachlos | Zendy; Ruth M. Risueño | Zendy; Sarah Laronde | Zendy; Zoya Shapovalova | Zendy; JongHee Lee | Zendy; Jennifer Russell | Zendy; Monika Malig | Zendy; Jamie McNicol | Zendy; Aline FiebigComyn | Zendy; Monica Graham | Zendy; Marilyne LevadouxMartin | Zendy; Jung Bok Lee | Zendy; Andrew O. Giacomelli | Zendy; John A. Hassell | Zendy; Daniela Fischer-Russell | Zendy; Michael Trus | Zendy; Ronan Foley | Zendy; Brian Leber | Zendy; Anargyros Xenocostas | Zendy; Eric D. Brown | Zendy; Tony Collins | Zendy; Mickie Bhatia | Zendy

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Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells

Author(s) -

Eleftherios Sachlos,

Ruth M. Risueño,

Sarah Laronde,

Zoya Shapovalova,

JongHee Lee,

Jennifer Russell,

Monika Malig,

Jamie McNicol,

Aline FiebigComyn,

Monica Graham,

Marilyne LevadouxMartin,

Jung Bok Lee,

Andrew O. Giacomelli,

John A. Hassell,

Daniela Fischer-Russell,

Michael Trus,

Ronan Foley,

Brian Leber,

Anargyros Xenocostas,

Eric D. Brown,

Tony Collins,

Mickie Bhatia

Publication year - 2012

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2012.03.049

Subject(s) - biology , dopamine , identification (biology) , dopamine receptor , stem cell , cancer stem cell , cancer , cancer cell , dopamine receptor d2 , computational biology , pharmacology , microbiology and biotechnology , neuroscience , genetics , ecology

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.

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