Abstract 2578: Berberine suppress the colon cancer proliferation through activating AMPK.
Authors: Li Weidong , Hua Baojin , Lin Hongsheng , Hou Wei , Jia Libin , Young Matthew R. , Colburn Nancy H. 
Published: August 2014

Background and Objectives: Numerous clinical studies and in vitro study have shown efficacy of Berberine, an isoquinoline alkaloid isolated from plants, in treating multiple diseases. Berberine possesses anti-diabetic, anti-inflammatory and anti-tumor properties. AMP-activated protein kinase (AMPK) is a cellular energy sensor that exists in almost all eukaryotes and is a potential therapeutic target for cancer. Berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity. Herein, this study explores whether the therapeutic role of Berberine on colon cancer is linked to the activation of AMPK signal pathway. Methods: In vitro studies: Three human colorectal cancer cell (CRC) lines (HCT116, SW480, LOVO) were treated with Berberine (0μM to 100μM) and cell proliferation assay was used to evaluate the inhibition effects on cell growth. The CRC lines were then treated with Berberine (0 to 60μM), for 24h or 48h, after which AMPK activation was measured by western blotting. In vivo studies: we used the azoxymethane-dextran sulfate sodium (AOM/DSS) mouse model of colitis induced colon cancer to explore the effects of Berberine on colon carcinogenesis. After DSS exposure, the FVB mice were randomly divided into two groups (N=19) and treated with Berberine (40mg/kg) or water for 10 weeks. After 10 weeks, all the mice were euthanized, the colon tissues were collected and the tumor numbers and tumor sizes were observed under microscopy.

Results: In vitro studies: Berberine inhibited the growth of the three CRC lines with an IC50 around 30μM. Berberine activated AMPK in a dose-dependent and time-dependent manner. In addition, mTOR, a downstream target of AMPK, was down-regulated by Berberine in a dose-dependent and time-dependent manner. Furthermore, 4EBP1 and p70s6kinase, downstream target of mTOR, were also down-regulated by

Berberine treatment in three colon cancer cell lines, whereas the MAPK pathway was not affected by Berberine. In vivo studies: Berberine treated mice showed a significant reduction of tumor numbers (60% reduction, p=0.013) and in tumor size (49% reduction for &lt;2mm, p=0.034; 94% for 2-4mm, p=0.006; and 100% for &gt;4mm p=0.024) compare to vehicle treated mice.

Conclusions: We have provided evidence that Berberine inhibits colon cancer cell growth and decrease AOM/DSS induced tumor numbers and tumor size. Our data suggest that Berberine suppresses colon epithelial proliferation via inhibition of mTOR through the activation of AMPK. Similar anticancer activity has been reported for Metformin, another antidiabetic drug that activates AMPK and inhibits mTOR signaling. Metformin is currently being tested in clinical trials for preventing cancer. In conclusion, Berberine might offer a safe and promising candidate for chemoprevention of colon cancer.

Citation Format: Weidong Li, Baojin Hua, Hongsheng Lin, Wei Hou, Libin Jia, Matthew R. Young, Nancy H. Colburn. Berberine suppress the colon cancer proliferation through activating AMPK. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2578. doi:10.1158/1538-7445.AM2013-2578