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Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis.

Authors :
Bin Li
Colin A Flaveny
Camilla Giambelli
Dennis Liang Fei
Lu Han
Brian I Hang
Feng Bai
Xin-Hai Pei
Vania Nose
Oname Burlingame
Anthony J Capobianco
Darren Orton
Ethan Lee
David J Robbins
Source :
PLoS ONE, Vol 9, Iss 7, p e101969 (2014)
Publication Year :
2014
Publisher :
Public Library of Science (PLoS), 2014.

Abstract

Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
9
Issue :
7
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.0534dfbdefa84db8a2507a5d09cc0d62
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0101969