Anticancer effects of berberine on human cholangiocarcinoma cells and mouse model

Abstract

Background and Aim: Cholangiocarcinoma (CCA) is an uncommon epithelial cell malignancy arising from the bile duct that is resistant to chemotherapy. So, there are no highly effective therapeutic agents for CCA. Recently, many of natural compounds including of berberine have attracted the attention of researchers and their use has increased during the past decades. Berberine is isolated from the stems, rhizomes, and roots of several plants such as Coptis chinensis which has been used as a therapeutic agent in the treatment of bacterial infections, diabetes, cardiovascular, and inflammatory diseases. Previous other studies have consistently reported the anticancer effect of berberine on various tumors such as breast, cervical, colon, hepatoma, lung, and ovarian cancer cells through inhibition of proliferation, migration, and invasion. However, little is known about the anticancer activities of berberine in CCA. The purpose of this study was to explore the effects and underlying mechanism of berberine on CCA. Methods: Human CCA cell lines (SNU-308, -478, -1079, and -1196) were used in this study. Cell viability was determined by MTT assay and the long-term proliferation of cells was determined by colony formation assay. Moreover, the cancer cell migration was examined by wound healing assay. MMP-9 and -2 activities were examined by zymography. The mRNA expression of MMP-9, MMP-2, Bax, Bcl-2, Capsae-9, Caspase-3, Beclin-1, LC3-II, and Snail1 was measured by qRT-PCR. Results: Berberine inhibited cell proliferation, migration, and colony formation in various CCA cell lines and also increased Bax, Caspase-9, -3 in SNU-478 cells. Berberine blocked MMP-9 activity in SNU-478 cells. In the xenograft model, berberine inhibited tumor growth and it increased Bax, Bcl-2, Caspase-9, Caspase-3, and decreased Snail1 in SNU-478 xenograft tumor model. Conclusion: This study suggested that berberine inhibits cell proliferation, migration, colony formation through mechanisms of apoptosis and autophagy in vitro and in vivo model. Therefore, berberine might be a potential therapeutic agent to treat patients with this devastating malignancy. Keywords: Cholangiocarcinoma, Berberine, Apoptosis, Migration