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.

Multiple Effects of Berberine Derivatives on Colon Cancer Cells

“…We describe here for the first time that the BBR derivatives NAX012, 14, and 18 affect cell cycle distribution in a p53 -dependent manner, in agreement with published data for the lead compound BBR [7, 40–42]. …”

“…These observations are in line with previous reports showing that BBR itself promotes the activation of procaspase 9 and mitochondria deregulation, typically observed in the intrinsic subroutine of apoptosis [19], although in some experimental systems BBR proved to activate the extrinsic pathway [46, 47]. The proapoptotic effect of BBR on cancer cells was reported to be associated with the modulation of JNK/p38-redox/ROS process, HER2/PI3K/AKT signaling, p53 -regulated factors and NF- κ B, AP-1, Wnt, and COX-2 proteins [3, 7, 22, 40, 42]. …”

Evaluation of the anti-cancer potential of <i>Mahonia aquifolium</i> extracts via apoptosis and anti-angiogenesis

“…It has been shown that berberine blocks Wnt/β-catenin signalling, inhibits cell migration (Park et al, 2012;Albring et al, 2013) and has the ability to regulate cell attachment through zonula occludens 1 protein (ZO-1) (Liu et al, 2009). Berberine can activate ZO-1, helps in the formation of tight junctions between cells and reduces cell mobility.…”

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

“…Phytic acid is a product of rice bran known to inhibit β-catenin during AOM-induced colon cancer (Saad et al, 2013;Shafie et al, 2013). Berberine acts as a natural inhibitor of Wnt/β-catenin signaling in HCT-116 colon carcinoma cells (Albring et al, 2013). The antiproliferative and antitumor activities of 2-hydroxycinnamaldehyde (1), a phenylpropanoid isolated from the bark of Cinnamomum cassia was found to inhibit β-catenin/T-cell factor (TCF) transcriptional activity in HCT116 colon cancer cell line .…”