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Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth

Item Type:Article
Title:Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth
Creators Name:Waaler, J. and Machon, O. and von Kries, J.P. and Wilson, S.R. and Lundenes, E. and Wedlich, D. and Gradl, D. and Paulsen, J.E. and Machonova, O. and Dembinski, J.L. and Dinh, H. and Krauss, S.
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 beta-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.
Keywords:Cell Division, Tumor Cell Line, Colorectal Neoplasms, Signal Transduction, Wnt Proteins, Animals, Mice
Source:Cancer Research
ISSN:0008-5472
Publisher:American Association for Cancer Research (U.S.A.)
Volume:71
Number:1
Page Range:197-205
Date:1 January 2011
Official Publication:https://doi.org/10.1158/0008-5472.CAN-10-1282
PubMed:View item in PubMed

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