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

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.

Anti-tumor Effects of Penfluridol through Dysregulation of Cholesterol Homeostasis

“…transformation (Sachlos et al, 2012). These data suggest that APDs might have a potential anti-tumor value for clinical treatment.…”

Smac Mimetics in Combination with TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma

“…Although the CSCs represent a small proportion of the tumor cells, they are key players in tumor initiation, recurrence, and metastasis (8)(9)(10)(11)(12). Therefore, CSCs have been considered as an important therapeutic target in anticancer treatments (6,9,(13)(14)(15)(16). Many compounds have been shown to selectively target CSCs in cancers such as salinomycin (6), TbRI inhibitors (9), lupeol (14), sulforaphane (15), thioridazine (16), and others.…”

“…Therefore, CSCs have been considered as an important therapeutic target in anticancer treatments (6,9,(13)(14)(15)(16). Many compounds have been shown to selectively target CSCs in cancers such as salinomycin (6), TbRI inhibitors (9), lupeol (14), sulforaphane (15), thioridazine (16), and others.…”

Dopamine receptor D 3 regulates endocytic sorting by a Prazosin-sensitive interaction with the coatomer COPI

“…com) as well as HeLa cells (Fig. 3B and SI Appendix, SI Materials and Methods) (19) and other cancer cells (20), suggesting that it might play a broader role. To confirm that our observations were not caused by off-target effects of the siRNAs targeting this receptor, we constructed a cell line that expressed an RNAi-resistant GFP-DRD3 allele (SI Appendix, SI Materials and Methods).…”