RESUMO
Aberrant activation of the canonical Wnt/ß-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 ß-catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/ß-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/ß-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 µM. Berberine inhibited ß-catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active ß-catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on ß-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/ß-catenin signaling in tumorigenesis.
