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

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• 作者：Eleftherios Sachlos¹ ; Ruth  ; M. Risueñ ; o¹ ; Sarah Laronde¹ ; Zoya Shapovalova¹ ; Jong-Hee Lee¹ ; Jennifer Russell¹ ; Monika Malig¹ ; Jamie  ; D. McNicol¹ ; Aline Fiebig-Comyn¹ ; Monica Graham¹ ; Marilyne Levadoux-Martin¹ ; Jung  ; Bok Lee¹ ; Andrew  ; O. Giacomelli² ; John  ; A. Hassell² ; Daniela Fischer-Russell¹ ; Michael  ; R. Trus³ ; Ronan Foley³ ; Brian Leber³ ; Anargyros Xenocostas⁴ ; Eric  ; D. Brown² ; Tony  ; J. Collins¹ ; Mickie Bhatia¹ ; ² ; ^{mbhatia@mcmaster.ca}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：8 June, 2012
• 卷：149
• 期：6
• 页码：1284-1297
• 文件大小：2051 K

摘要

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Summary

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聽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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