title: Anti-leprosy drug clofazimine inhibits growth of triple-negative breast cancer cells via inhibition of canonical Wnt signaling.
abstract: Research on existing drugs often discovers novel mechanisms of their action and leads to the expansion of their therapeutic scope and subsequent remarketing. The Wnt signaling pathway is of the immediate therapeutic relevance, as it plays critical roles in cancer development and progression. However, drugs which disrupt this pathway are unavailable despite the high demand. Here we report an attempt to identify antagonists of the Wnt-FZD interaction among the library of the FDA-approved drugs. We performed an in silico screening which brought up several potential antagonists of the ligand-receptor interaction. 14 of these substances were tested using the TopFlash luciferase reporter assay and four of them identified as active and specific inhibitors of the Wnt3a-induced signaling. However, further analysis through GTP-binding and β-catenin stabilization assays showed that the compounds do not target the Wnt-FZD pair, but inhibit the signaling at downstream levels. We further describe the previously unknown inhibitory activity of an anti-leprosy drug clofazimine in the Wnt pathway and provide data demonstrating its efficiency in suppressing growth of Wnt-dependent triple-negative breast cancer cells. These data provide a basis for further investigations of the efficiency of clofazimine in treatment of Wnt-dependent cancers.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, Lausanne 1005, Switzerland.
authors.forename: A V
authors.initials: AV
authors.lastname: Koval
authors.affiliation: Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG) 88 Dr. Aiguader, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Vlasov
authors.affiliation: Moscow Institute of Physics and Technology (State University), Moscow, Russia.
authors.forename: P
authors.initials: P
authors.lastname: Shichkova
authors.affiliation: Municipal budget institution of general education gymnasium "Pushchino", Pushchino, Russia.
authors.forename: S
authors.initials: S
authors.lastname: Khunderyakova
authors.affiliation: National Research University Higher School of Economics, Moscow, Russia.
authors.forename: Y
authors.initials: Y
authors.lastname: Markov
authors.affiliation: Moscow Institute of Physics and Technology (State University), Moscow, Russia.
authors.forename: J
authors.initials: J
authors.lastname: Panchenko
authors.affiliation: Kazan Federal University, Kazan, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Volodina
authors.affiliation: Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG) 88 Dr. Aiguader, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 23 Pg. Lluís Companys, 08010 Barcelona, Spain.
authors.forename: F A
authors.initials: FA
authors.lastname: Kondrashov
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, Lausanne 1005, Switzerland; Institute of Protein Research, Russian Academy of Science, Instituskaya 4, Moscow Region, Pushchino 142290, Russia. Electronic address: vladimir.katanaev@unil.ch.
authors.forename: V L
authors.initials: VL
authors.lastname: Katanaev
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002991:Clofazimine / Q000494:pharmacology* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D007917:Leprostatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology*; D060509:Wnt3A Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*
chemical_list: D006131:Growth Inhibitors; D007917:Leprostatic Agents; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D002991:Clofazimine
keywords: Breast cancer; Clofazimine; In silico screening; Wnt signaling