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, Michael Detmar

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1007-1022
Number of pages16
JournalOncotarget
Volume8
Issue number1
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Benztropine mesylate
  • Breast cancer stem cells
  • Cell-based phenotypic screening
  • NCI DTP-diversity set II
  • Prestwick library

ASJC Scopus subject areas

  • Oncology

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