Berberine inhibits colitis-associated tumorigenesis via suppressing inflammatory responses and the consequent EGFR signaling-involved tumor cell growth

Abstract

The anti-inflammatory and anti-tumor effects of berberine, a traditional Chinese medicine, were separately discovered in pathological intestinal tissues. However, whether the anti-inflammatory effect of berberine contributes to its anti-tumor effect on colitis-associated colorectal cancer (CACRC) remains unknown. In the present study, we found that berberine effectively inhibited colitis-associated tumorigenesis and colonic epithelium hyperproliferation in dextran sulfate sodium (DSS)-treated Apc mice. A mechanistic study identified that these inhibitory effects of berberine occurred through blocking interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in colonic macrophages. An in vitro study on cell lines identified that berberine treatment of Raw 264.7 macrophages resulted in conditioned media with fewer proliferative effects on a cell line with a heterozygous Apc mutation (Immorto-Min colonic epithelium, IMCE). EGFR-ERK signaling act downstream of berberine/pro-inflammatory cytokines axis to regulate CACRC cell proliferation. Furthermore, in vivo administration of IL-6 to DSS-treated Apc mice effectively weakened the inhibitory effects of berberine on tumorigenesis and EGFR-ERK signaling in colon tissues. Altogether, the results of our studies have revealed that berberine inhibits the development of CACRC by interfering with inflammatory response-driven EGFR signaling in tumor cell growth. The findings of this study support the possibility that berberine and other anti-inflammatory drugs may be beneficial in the treatment of CACRC.

The Effects of Berberine on the Gut Microbiota in Apc min/+ Mice Fed with a High Fat Diet

“…It has been used for the treatment of intestinal infections for a long time in China and is one of the most popular herbal supplements for children in America [ 11 ]. Accumulating evidence has proven that BBR can suppress colon epithelial proliferation and tumorigenesis through the inhibition of epidermal growth factor receptor (EGFR) signaling, the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the activation of AMP-activated protein kinase (AMPK) [ 12 , 13 , 14 ]. However, we cannot fully explain its clinical efficacy, because its bioavailability is very low as a result of poor solubility and membrane permeability [ 15 ].…”

Regulation of Akt/FoxO3a/Skp2 Axis Is Critically Involved in Berberine-Induced Cell Cycle Arrest in Hepatocellular Carcinoma Cells

“…Accumulated evidence has emerged, illuminating anti-cancer effects of phytochemical-berberine (BBR) [ 6 ], which is an isoquinoline type of botanical alkaloid present in many traditional Chinese medicines as the major bioactive compound. BBR has several potent pharmacological functions and has been used for its antidiabetic, antimicrobial, antidiabetic, antidiarrheal and anti-inflammatory activities [ 7 , 8 , 9 ]. Additionally, BBR has been reported to possess anti-tumor activity in multiple types of cancers including HCC [ 10 , 11 ].…”

hERG1 is involved in the pathophysiological process and inhibited by berberine in SKOV3 cells

“…Over the past decades, BBR has drawn extensive attention due to its antitumorigenic effects in various types of human cancer cells and animal models (33,34). Treatment with BBR has been reported to act on numerous targets and signaling pathways underlying pathophysiological process, including proliferation, apoptosis, angiogenesis, migration and invasion in a variety of cancer cells (35)(36)(37). In our previous study, BBR was observed to exert a strong inhibitory effect on hERG potassium channels (22,38,39), which are often aberrantly expressed in carcinoma.…”