The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer

Article Article scientifique Article The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer eng 2014 author Melotti Alice 727921 author Mas Christophe 515567 author Kuciak Monika 771709 author Lorente Trigos Aiala 672171 author Borges Grazina Ana Isabel 135554 author Ruiz Altaba Ariel 135639 1263-1278 10.15252/emmm.201404084 25143352 1757-4676 Constitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCF(VP16). Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers. Dewey 576.5 135 Département de médecine génétique et développement 21D false 446 Stemness in developpment and disease: Signalling, reprogramming and mechanisms of metastases 776 EMBO molecular medicine 6 10 058875b0-78cc-4b74-9b5f-e73056b782cf Article (Published version) Restricted Melotti,Mas,.pdf 1079759 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

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The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer	EMBO molecular medicine			2014	720	5

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