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

July 27, 2012

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 invivo 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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Ethan Perlstein
08.03.12 4:01 pm

The chief difference between cancer stem cells and normal stem cells is that the
former perpetually self renew and disregard differentiation signals to which the latter faithfully respond. This study uses a
human pluripotent stem cell line as an in vitro surrogate for cancer stem cells for the purposes of chemical screening. I find nothing
wrong with the premise of this paper: selective killing of cancer stem cells that refuel tumor growth, while sparing normal stem cells that reconstitute healthy tissue, seems like a prudent therapeutic course of action for cancer. However, I’m deeply skeptical of the claim that the selective killing of cancer stem cells by phenothiazine antipsychotics is solely via inhibition of dopamine receptors.

First, the EC50 (half-maximal effective concentration) of the phenothiazine screening hits is not sub-micromolar. Like many small-scale academic screening efforts,
the authors used a collection of known bioactives, which get screened all the time, typically in the 10-25µM range for cell-based assays. The authors used 10µM as
their potency cutoff. 10µM is an important number because as the authors admit, phenothiazine antipsychotics like thioridazine (figure above the fold, middle compound) are notorious for their polypharmacology, i.e., their ability to bind more than one drug target. 10µM is several orders of magnitude above the binding constant for dopamine receptors. And the polypharmacology of phenothiazine antipsychotics is not limited to protein targets, because phenothiazines also accumulate in cell membrane. For more of this contrarian view, see the comment thread of Derek Lowe’s recent blog review of this paper. (Look over to the right side panel of this page ——->).

Second, the target validation strategy is roundabout, correlative and syllogistic. Basically, the authors’ argument went something like this: the literature says phenothiazine antipsychotics target dopamine receptors; cancer stem cells
express dopamine receptors and can be induced to differentiate by thioridazine; normal stem cells don’t express dopamine receptors and can’t be induced to differentiate by thioridazine; ergo, thioridazine induces differentiation via dopamine receptor inhibition.

I’m sure there are many proteins that are expressed selectively in cancer stem cells vs normal stem cells, but that doesn’t mean they are the locus of a compound’s pharmacological effects. Why didn’t they try to knockdown dopamine receptors in cancer stem cells? Or block dopamine receptors with highly specific antibodies? Most tellingly, clozapine, an atypical antipsychotic and dopamine receptor antagonist (among other activities), also exhibited selective killing of cancer stem cells but the authors used it at 100µM (and only mentioned this little fact in tiny font in the figure itself)! Hmm.


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