title: Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth.
abstract: Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role in tumor cell growth and progression. Here we report the identification of 2 new small molecules that specifically inhibit canonical Wnt pathway at the level of the destruction complex. Specificity was verified in various cellular reporter systems, a Xenopus double-axis formation assay and a gene expression profile analysis. In human colorectal cancer (CRC) cells, the new compounds JW67 and JW74 rapidly reduced active β-catenin with a subsequent downregulation of Wnt target genes, including AXIN2, SP5, and NKD1. Notably, AXIN2 protein levels were strongly increased after compound exposure. Long-term treatment with JW74 inhibited the growth of tumor cells in both a mouse xenograft model of CRC and in Apc(Min) mice (multiple intestinal neoplasia, Min). Our findings rationalize further preclinical and clinical evaluation of these new compounds as novel modalities for cancer treatment.
authors.affiliation: Section for Cellular and Genetic Therapy, Institute of Microbiology, Oslo University Hospital, and Norwegian Center for Stem Cell Research, Forskningsparken, Oslo, Norway. jo.waaler@rr-research.no
authors.forename: Jo
authors.initials: J
authors.lastname: Waaler
authors.forename: Ondrej
authors.initials: O
authors.lastname: Machon
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: von Kries
authors.forename: Steven Ray
authors.initials: SR
authors.lastname: Wilson
authors.forename: Elsa
authors.initials: E
authors.lastname: Lundenes
authors.forename: Doris
authors.initials: D
authors.lastname: Wedlich
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gradl
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Paulsen
authors.forename: Olga
authors.initials: O
authors.lastname: Machonova
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dembinski
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.forename: Stefan
authors.initials: S
authors.lastname: Krauss
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000593016:JW74 compound; D010069:Oxadiazoles; D014230:Triazoles; D051153:Wnt Proteins