Research Papers:

New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate

Jihong Cui, Maija Hollmén, Lina Li, Yong Chen, Steven T. Proulx, Daniel Reker, Gisbert Schneider and Michael Detmar _

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Oncotarget. 2017; 8:1007-1022. https://doi.org/10.18632/oncotarget.13537

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Jihong Cui1, Maija Hollmén1, Lina Li1, Yong Chen1, Steven T. Proulx1, Daniel Reker1, Gisbert Schneider1, Michael Detmar1

1Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich, Zürich, Switzerland

Correspondence to:

Michael Detmar, email: [email protected]

Keywords: Prestwick library, NCI DTP-diversity set II, cell-based phenotypic screening, benztropine mesylate, breast cancer stem cells

Received: April 17, 2016    Accepted: November 06, 2016    Published: November 24, 2016


Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24- phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents.

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