title: Berberine acts as a natural inhibitor of Wnt/β-catenin signaling--identification of more active 13-arylalkyl derivatives.
abstract: Aberrant activation of the canonical Wnt/β-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 β-catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/β-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/β-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 β-catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active β-catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on β-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/β-catenin signaling in tumorigenesis.
authors: Institute of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena, Nonnenplan 2-4, 07743, Jena, Germany.
authors: Kai Frederik
authors: KF
authors: Albring
authors: Julia
authors: J
authors: Weidemüller
authors: Sonnhild
authors: S
authors: Mittag
authors: Jörg
authors: J
authors: Weiske
authors: Karlheinz
authors: K
authors: Friedrich
authors: M Cristina
authors: MC
authors: Geroni
authors: Paolo
authors: P
authors: Lombardi
authors: Otmar
authors: O
authors: Huber
mesh_terms: D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin; D001599:Berberine
keywords: E-cadherin; Wnt; berberine; colorectal cancer; isoquinoline alkaloid; phytochemicals; plant micronutrient; β-catenin