Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations
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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. Cancer Res; 71(12); 4172–82. ©2011 AACR.
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Niclosamide decreases Dvl-2 and β-catenin expression and is now in clinical trials for CRC.
“niclosamide that decreases Dv1-2 and β-catenin expression [114] and now is in clinical trials for CRC [115]”
From Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment (2024) · cites this paper as [114]
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- Authors
- Osada, T., Chen, M., Yang, X. Y., Spasojevic, I., Vandeusen, J. B., Hsu, D., Clary, B. M., Clay, T. M., Chen, W., Morse, M. A., & Lyerly, H. K.
- Affiliations
- Duke University (US)
- Authors' Affiliations: 1Department of Surgery, 2Department of Medicine, Division of Gastroenterology, 3Department of Medicine, Clinical Pharmacology Lab, 4Department of Medicine, Division of Medical Oncology, and 5Department of Immunology, Duke University Medical Center, Durham, North Carolina
- Corresponding author
- Lyerly, H. Kim
- ORCID
- Venue
- Cancer Research
- Published
- 2011-06-14
- Volume
- 71
- Issue
- 12
- Pages
- 4172-4182
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3117125
- OpenAlex
- W2121419977
- Cited by
- 271
- References
- 33
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 22 · 2023: 17 · 2022: 19 · 2021: 22 · 2020: 20 · 2019: 18 · 2018: 20 · 2017: 23 · 2016: 32 · 2015: 20 · 2014: 16 · 2013: 14 · 2012: 8
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA078673, K12CA100639, P30CA014236)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- niclosamide, Wnt/β-catenin signaling, APC mutation, colorectal cancer, Dishevelled 2, anticancer activity, drug repurposing, antiproliferative activity, metastatic colon cancer, oral drug delivery
- MeSH terms
- Dishevelled Proteins, Oxaliplatin, Animals, Anthelmintics, Antineoplastic Agents, Fibroblasts, Humans, Mutation, Niclosamide, Organoplatinum Compounds, Phosphoproteins, Colorectal Neoplasms, Signal Transduction, NF-kappa B, Mice, SCID, Genes, APC, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Wnt Proteins, beta Catenin, Mice, TOR Serine-Threonine Kinases
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