Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations
Identifieur interne : 001414 ( Main/Exploration ); précédent : 001413; suivant : 001415Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations
Auteurs : Takuya Osada ; Minyong Chen ; Xiao Yi Yang ; Ivan Spasojevic ; Jeffrey B. Vandeusen ; David Hsu ; Bryan M. Clary ; Timothy M. Clay ; Wei Chen ; Michael A. Morse ; H. Kim LyerlySource :
- Cancer research [ 0008-5472 ] ; 2011.
Abstract
Wnt/β-catenin pathway activation caused by APC mutations occurs in approximately 80% of sporadic colorectal cancers. The anti-helminth 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 if niclosamide could inhibit the Wnt/ β-catenin pathway in human colorectal cancers 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 anti-proliferative effects in human colon cancer cell lines and colorectal cancer 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 anti-proliferative effects in these colorectal cancer model systems. In mice implanted with human colorectal cancer 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 treatment of colorectal cancer.
Url:
DOI: 10.1158/0008-5472.CAN-10-3978
PubMed: 21531761
PubMed Central: 3117125
Affiliations:
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Vandeusen</name><affiliation><nlm:aff id="A4">Department of Medicine, Division of Medical Oncology, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation></author><author><name sortKey="Hsu, David" sort="Hsu, David" uniqKey="Hsu D" first="David" last="Hsu">David Hsu</name><affiliation><nlm:aff id="A4">Department of Medicine, Division of Medical Oncology, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation></author><author><name sortKey="Clary, Bryan M" sort="Clary, Bryan M" uniqKey="Clary B" first="Bryan M." last="Clary">Bryan M. 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Clay</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation><affiliation><nlm:aff id="A5">Department of Immunology, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation></author><author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><affiliation><nlm:aff id="A2">Department of Medicine, Division of Gastroenterology, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation></author><author><name sortKey="Morse, Michael A" sort="Morse, Michael A" uniqKey="Morse M" first="Michael A." last="Morse">Michael A. Morse</name><affiliation><nlm:aff id="A4">Department of Medicine, Division of Medical Oncology, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation></author><author><name sortKey="Lyerly, H Kim" sort="Lyerly, H Kim" uniqKey="Lyerly H" first="H. Kim" last="Lyerly">H. Kim Lyerly</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation><affiliation><nlm:aff id="A5">Department of Immunology, Duke University Medical Center</nlm:aff><wicri:noCountry code="subfield">Duke University Medical Center</wicri:noCountry></affiliation></author></analytic><series><title level="j">Cancer research</title><idno type="ISSN">0008-5472</idno><idno type="eISSN">1538-7445</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Wnt/β-catenin pathway activation caused by APC mutations occurs in approximately 80% of sporadic colorectal cancers. The anti-helminth 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 if niclosamide could inhibit the Wnt/ β-catenin pathway in human colorectal cancers 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 anti-proliferative effects in human colon cancer cell lines and colorectal cancer 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 anti-proliferative effects in these colorectal cancer model systems. In mice implanted with human colorectal cancer 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 treatment of colorectal cancer.</p></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Chen, Minyong" sort="Chen, Minyong" uniqKey="Chen M" first="Minyong" last="Chen">Minyong Chen</name><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><name sortKey="Clary, Bryan M" sort="Clary, Bryan M" uniqKey="Clary B" first="Bryan M." last="Clary">Bryan M. Clary</name><name sortKey="Clay, Timothy M" sort="Clay, Timothy M" uniqKey="Clay T" first="Timothy M." last="Clay">Timothy M. Clay</name><name sortKey="Hsu, David" sort="Hsu, David" uniqKey="Hsu D" first="David" last="Hsu">David Hsu</name><name sortKey="Lyerly, H Kim" sort="Lyerly, H Kim" uniqKey="Lyerly H" first="H. Kim" last="Lyerly">H. Kim Lyerly</name><name sortKey="Morse, Michael A" sort="Morse, Michael A" uniqKey="Morse M" first="Michael A." last="Morse">Michael A. Morse</name><name sortKey="Osada, Takuya" sort="Osada, Takuya" uniqKey="Osada T" first="Takuya" last="Osada">Takuya Osada</name><name sortKey="Spasojevic, Ivan" sort="Spasojevic, Ivan" uniqKey="Spasojevic I" first="Ivan" last="Spasojevic">Ivan Spasojevic</name><name sortKey="Vandeusen, Jeffrey B" sort="Vandeusen, Jeffrey B" uniqKey="Vandeusen J" first="Jeffrey B." last="Vandeusen">Jeffrey B. Vandeusen</name><name sortKey="Yang, Xiao Yi" sort="Yang, Xiao Yi" uniqKey="Yang X" first="Xiao Yi" last="Yang">Xiao Yi Yang</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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