Berberine acts as a natural inhibitor of Wnt/β-catenin signaling-Identification of more active 13-arylalkyl derivatives

Aberrant activation of the canonical Wnt/-catenin signaling pathway has been reported for numerous tumors of different origins. In most cases, mutations in components of the Wnt signaling pathway or in -catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/-catenin signaling is of specific therapeutic interest. Herein, we investigated the plant-derived isoquinoline alkaloid berberine, which has been reported to have anticancer activity, and synthetic 13-arylalkyl derivatives thereof for their effects on Wnt/-catenin signaling. Berberine did not show major effects on viability of HEK-293 embryonic kidney and HCT116 colon carcinoma cells and was not toxic in concentrations up to 20 mu M. Berberine inhibited -catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active -catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on -catenin levels were low. A screen of synthetic 13-arylalkyl berberine derivatives identified compounds exhibiting activities superior to those of the naturally occurring parent substance with more than 100-fold lower EC50 values for Wnt-repression. Thus, berberine and its synthetic derivatives represent potential therapeutic agents to inhibit Wnt/-catenin signaling in tumorigenesis. (c) 2013 BioFactors, 39(6):652-662, 2013