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

Cui, Jihong; Hollmén, Maija; Li, Lina; Chen, Yong; Proulx, Steven T; Reker, Daniel; Schneider, Gisbert; Detmar, Michael (2017). New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate. OncoTarget, 8(1), pp. 1007-1022. Impact Journals LLC 10.18632/oncotarget.13537

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Proulx, Steven Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1949-2553

Publisher:

Impact Journals LLC

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

21 Oct 2020 12:10

Last Modified:

21 Oct 2020 13:32

Publisher DOI:

10.18632/oncotarget.13537

PubMed ID:

27894093

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.147199

URI:

https://boris.unibe.ch/id/eprint/147199

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