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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations</title><author><name sortKey="Osada, Takuya" sort="Osada, Takuya" uniqKey="Osada T" first="Takuya" last="Osada">Takuya Osada</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Chen, Minyong" sort="Chen, Minyong" uniqKey="Chen M" first="Minyong" last="Chen">Minyong Chen</name><affiliation><nlm:aff id="A2">Department of Medicine, Division of Gastroenterology, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Yang, Xiao Yi" sort="Yang, Xiao Yi" uniqKey="Yang X" first="Xiao Yi" last="Yang">Xiao Yi Yang</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Spasojevic, Ivan" sort="Spasojevic, Ivan" uniqKey="Spasojevic I" first="Ivan" last="Spasojevic">Ivan Spasojevic</name><affiliation><nlm:aff id="A3">Department of Medicine, Clinical Pharmacology Lab, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Vandeusen, Jeffrey B" sort="Vandeusen, Jeffrey B" uniqKey="Vandeusen J" first="Jeffrey B." last="Vandeusen">Jeffrey B. Vandeusen</name><affiliation><nlm:aff id="A4">Department of Medicine, Division of Medical Oncology, Duke University Medical Center</nlm:aff></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></affiliation></author><author><name sortKey="Clary, Bryan M" sort="Clary, Bryan M" uniqKey="Clary B" first="Bryan M." last="Clary">Bryan M. Clary</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Clay, Timothy M" sort="Clay, Timothy M" uniqKey="Clay T" first="Timothy M." last="Clay">Timothy M. Clay</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Department of Immunology, Duke University Medical Center</nlm:aff></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></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></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></affiliation><affiliation><nlm:aff id="A5">Department of Immunology, Duke University Medical Center</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21531761</idno><idno type="pmc">3117125</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117125</idno><idno type="RBID">PMC:3117125</idno><idno type="doi">10.1158/0008-5472.CAN-10-3978</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000387</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000387</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations</title><author><name sortKey="Osada, Takuya" sort="Osada, Takuya" uniqKey="Osada T" first="Takuya" last="Osada">Takuya Osada</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Chen, Minyong" sort="Chen, Minyong" uniqKey="Chen M" first="Minyong" last="Chen">Minyong Chen</name><affiliation><nlm:aff id="A2">Department of Medicine, Division of Gastroenterology, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Yang, Xiao Yi" sort="Yang, Xiao Yi" uniqKey="Yang X" first="Xiao Yi" last="Yang">Xiao Yi Yang</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Spasojevic, Ivan" sort="Spasojevic, Ivan" uniqKey="Spasojevic I" first="Ivan" last="Spasojevic">Ivan Spasojevic</name><affiliation><nlm:aff id="A3">Department of Medicine, Clinical Pharmacology Lab, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Vandeusen, Jeffrey B" sort="Vandeusen, Jeffrey B" uniqKey="Vandeusen J" first="Jeffrey B." last="Vandeusen">Jeffrey B. Vandeusen</name><affiliation><nlm:aff id="A4">Department of Medicine, Division of Medical Oncology, Duke University Medical Center</nlm:aff></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></affiliation></author><author><name sortKey="Clary, Bryan M" sort="Clary, Bryan M" uniqKey="Clary B" first="Bryan M." last="Clary">Bryan M. Clary</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation></author><author><name sortKey="Clay, Timothy M" sort="Clay, Timothy M" uniqKey="Clay T" first="Timothy M." last="Clay">Timothy M. Clay</name><affiliation><nlm:aff id="A1">Department of Surgery, Duke University Medical Center</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Department of Immunology, Duke University Medical Center</nlm:aff></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></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></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></affiliation><affiliation><nlm:aff id="A5">Department of Immunology, Duke University Medical Center</nlm:aff></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><pmc article-type="research-article" xml:lang="en"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">2984705R</journal-id><journal-id journal-id-type="pubmed-jr-id">2786</journal-id><journal-id journal-id-type="nlm-ta">Cancer Res</journal-id><journal-title-group><journal-title>Cancer research</journal-title></journal-title-group><issn pub-type="ppub">0008-5472</issn><issn pub-type="epub">1538-7445</issn></journal-meta><article-meta><article-id pub-id-type="pmid">21531761</article-id><article-id pub-id-type="pmc">3117125</article-id><article-id pub-id-type="doi">10.1158/0008-5472.CAN-10-3978</article-id><article-id pub-id-type="manuscript">NIHMS293098</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Osada</surname><given-names>Takuya</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Minyong</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Xiao Yi</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Spasojevic</surname><given-names>Ivan</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Vandeusen</surname><given-names>Jeffrey B.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Hsu</surname><given-names>David</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Clary</surname><given-names>Bryan M.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Clay</surname><given-names>Timothy M.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Morse</surname><given-names>Michael A.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Lyerly</surname><given-names>H. Kim</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A5">5</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Surgery, Duke University Medical Center</aff><aff id="A2"><label>2</label>Department of Medicine, Division of Gastroenterology, Duke University Medical Center</aff><aff id="A3"><label>3</label>Department of Medicine, Clinical Pharmacology Lab, Duke University Medical Center</aff><aff id="A4"><label>4</label>Department of Medicine, Division of Medical Oncology, Duke University Medical Center</aff><aff id="A5"><label>5</label>Department of Immunology, Duke University Medical Center</aff><author-notes><corresp id="CR1">Corresponding author address: H. Kim Lyerly 2424 Erwin Road, Suite 601, Durham, NC 27705 tel: 1-919-684-5613 fax: 1-919-684-5653 <email>lyerl001@mc.duke.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>2</day><month>5</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>29</day><month>4</month><year>2011</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>6</month><year>2011</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>6</month><year>2012</year></pub-date><volume>71</volume><issue>12</issue><fpage>4172</fpage><lpage>4182</lpage><abstract><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></abstract><funding-group><award-group><funding-source country="United States">National Cancer Institute : NCI</funding-source><award-id>P30 CA014236-37 || CA</award-id></award-group><award-group><funding-source country="United States">National Cancer Institute : NCI</funding-source><award-id>P01 CA078673-09 || CA</award-id></award-group><award-group><funding-source country="United States">National Cancer Institute : NCI</funding-source><award-id>P01 CA078673-08 || CA</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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