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McDonnell Foundation 21st Century Science Initiative in Brain Cancer\u2014Research Award"},{"name":"D\u00e9partement d'Instruction Publique de la R\u00e9publique et Canton of Gen\u00e8ve"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EMBO Mol Med"],"published-print":{"date-parts":[[2014,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Constitutive activation of canonical WNT\u2010TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT\u2010TCF antagonists in clinical use. We have performed a repositioning screen for WNT\u2010TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant\u2010negative TCF. We report that Ivermectin inhibits the expression of WNT\u2010TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCF\n                    <jats:sup>VP<\/jats:sup>\n                    <jats:sup>16<\/jats:sup>\n                    . Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C\u2010terminal \u03b2\u2010CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid\u2010sensitive manner, indicating its action involves protein phosphatases.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , Ivermectin selectively inhibits TCF\u2010dependent, but not TCF\u2010independent, xenograft growth without obvious side effects. Analysis of single semi\u2010synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti\u2010parasitic agent used by &gt;\u00a0200 million people against river blindness, our results suggest its additional use as a therapeutic WNT\u2010TCF pathway response blocker to treat WNT\u2010TCF\u2010dependent diseases including multiple cancers.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201404084","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T01:05:14Z","timestamp":1408583114000},"page":"1263-1278","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT\u2010TCF pathway responses in human cancer"],"prefix":"10.1038","volume":"6","author":[{"given":"Alice","family":"Melotti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Mas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Kuciak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiala","family":"Lorente\u2010Trigos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Borges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Ruiz i Altaba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,8,20]]},"reference":[{"key":"BFEMMM201404084_CR1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrc3419","volume":"13","author":"JN Anastas","year":"2013","unstructured":"Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. 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