Identification of Drugs Including a Dopamine Receptor Antagonist that Selectively Target Cancer Stem Cells
Menée in vitro et in vivo, cette étude suggère que la thioridazine, un médicament antipsychotique, est susceptible d'interagir de façon sélective avec les récepteurs à la dopamine présents à la surface des cellules souches de leucémie et de cancer du sein
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. º Neoplastic hPSCs provide a robust generalizable screening model for human CSCs º Compounds that induce hPSC differentiation selectively target somatic CSCs º Thioridazine selectively targets leukemic stem cells while sparing normal HSCs º Dopamine receptor pathway provides a candidate biomarker of human CSCs A chemical screen for compounds that selectively promote differentiation of human neoplastic stem cells identifies thioridazine, a known dopamine receptor antagonist and antipsychotic drug, as a candidate molecule for targeting cancer stem cells. Unexpectedly, dopamine receptors are found on leukemic and breast cancer stem cells and may serve as biomarkers for cancer stem cells as well as therapeutic targets.
Cell , résumé, 2011