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Summary
Selective targeting of cancer ste
m cells (CSCs) offers pro
mise for a new generation of therapeutics. However, assays for both hu
man CSCs and nor
mal ste
m cells that are a
menable to robust biological screens are li
mited. Using a discovery platfor
m that reveals differences between neoplastic and nor
mal hu
man pluripotent ste
m cells (hPSC), we identify s
mall
molecules fro
m libraries of known co
mpounds that induce differentiation to overco
me neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and i
mpairs hu
man so
matic CSCs capable of in聽vivo leuke
mic disease initiation while having no effect on nor
mal blood SCs. The drug antagonizes dopa
mine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopa
mine receptors
may serve as a bio
marker for diverse
malignancies, de
monstrate 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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