The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer
| Autor: | Ariel Ruiz i Altaba, Alice Melotti, Isabel Borges, Aiala Lorente-Trigos, Christophe Mas, Monika Kuciak |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Insecticides
Macrocyclic Compounds Beta-catenin animal structures Blotting Western Mice Nude Apoptosis Mice Inbred Strains Pharmacology Biology TCF/LEF family WNT Lactones Ivermectin Cyclin D1 In vivo Cell Line Tumor Neoplasms Onchocerciasis Ocular medicine Animals Humans cancer ddc:576.5 xenograft beta Catenin Research Articles Cell Proliferation Reverse Transcriptase Polymerase Chain Reaction Wnt signaling pathway Cancer TCF medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Wnt Proteins HEK293 Cells Mutation embryonic structures biology.protein Molecular Medicine Female Signal transduction TCF Transcription Factors HT29 Cells Signal Transduction medicine.drug |
| Zdroj: | EMBO Molecular Medicine, Vol. 6, No 10 (2014) pp. 1263-78 EMBO Molecular Medicine |
| ISSN: | 1757-4676 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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