Identification of N-[3-(3,4-Dihydroxyphenyl)-1-oxo-2-propenyl]-2-hydroxybenzamide (CGK-101) as a Small Molecule Inhibitor of the Wnt/β-catenin Pathway

Abstract

Colorectal cancer is the most prevalent type of cancer and the second leading cause of cancer-related mortalities in Western countries. 1 Current therapies for colorectal cancer rely on surgical resection, which is rarely curative in advanced disease, and traditional cytotoxic agents exhibit limited effects. Therefore, it is crucial to develop new therapeutic strategies that are based on defined molecular lesions. The development and progression of colorectal cancer are related to the accumulation of a series of genetic and epigenetic alterations. 2,3 Molecular lesions in the adenomatous polyposis coli (APC) gene are observed in most sporadic colorectal cancers as well as in familial adenomatous polyposis (FAP) and they appear early in the progression of this type of cancer. 4 In addition, the N-terminal phosphorylation motif of β-catenin is frequently mutated in colorectal cancer. 5 These alterations lead to the accumulation of β-catenin in the nucleus, where it forms a complex with T-cell factor/lymphocyte enhancer factor (TCF/LEF) family transcription factors. It then activates its target genes, such as c-myc, cyclin D1, and metalloproteinase-7, which play important roles in colorectal tumorigenesis and metastasis. 6-8 Thus, inhibition of the Wnt/β-catenin pathway, which is aberrantly up-regulated in colorectal cancer, is a potential therapeutic strategy for treating colorectal cancer. In this study, we used cell-based chemical screening to identify N-[3-(3,4-dihydroxyphenyl)-1-oxo-2-propenyl]-2hydroxybenzamide (CGK-101) as an inhibitor of the Wnt/βcatenin pathway. It has been reported that CGK-101, unique polyphenol found in oatmeal, has the effect for the prevention and improvement of muscular disorders and for the improvement of muscle function. 9 Also this compound exhibited epidermal growth factor receptor (EGFR) tyrosin kinase inhibitory activity. 10 CGK-101 attenuated β-catenin response transcription (CRT) that was increased by Wnt3aconditioned medium (Wnt3a-CM) and LiCl, which is an inhibitor of glycogen synthase kinase-3β (GSK-3β), by promoting intracellular β-catenin degradation. In addition, CGK-101 down-regulated the level of β-catenin, which resulted in the repression of the β-catenin/T cell factordependent gene cyclin D1 in HCT116 colon cancer cells and thus inhibited the proliferation of these cells. These results indicate that CGK-101 provide a novel therapeutic strategy for colon cancer via its suppression of the Wnt/β-catenin pathway.