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Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.

Authors
  • Osada, Takuya
  • Chen, Minyong
  • Yang, Xiao Yi
  • Spasojevic, Ivan
  • Vandeusen, Jeffrey B
  • Hsu, David
  • Clary, Bryan M
  • Clay, Timothy M
  • Chen, Wei
  • Morse, Michael A
  • Lyerly, H Kim
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jun 15, 2011
Volume
71
Issue
12
Pages
4172–4182
Identifiers
DOI: 10.1158/0008-5472.CAN-10-3978
PMID: 21531761
Source
Medline
License
Unknown

Abstract

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.

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