The preventive and curative potential of berberine and coptis on humanhepatocellular carcinoma

Abstract



Hepatocellular carcinoma (HCC) is the primary cancer of liver. It is the fifth common malignant tumor in men while seventh common in women. Aetiology of HCC is complex; however, it is now believed that sustained chronic liver injury and fibrosis are critically involved in the development of HCC. Prevention and treatment of HCC is far from desirable and prognosis remains poor. Coptis is a Chinese herbal Medicine which has been used for more than thousands years for clearing heats, dampness and toxics. Recently, studies from our group reported the hepatoprotective effect of Coptis and its major active component, berberine, on acute liver injury and berberine was extensively studied for their anti-tumor effect. However, there’s no comprehensive investigation focusing on the preventive and curative potential of berberine on HCC. Hence, here we hypothesized Coptis and berberine exhibits both preventive and curative effects on HCC. The prevention of HCC by berberine and Coptis may rely on their effects on chronic liver damage and fibrosis, and the curative action may depend on their actions on the angiogenesis, tumor growth and invasion of HCC. Both in vitro cell models and in vivo animal system were used in our study and some molecular events were investigated. We found that berberine and Coptis could significantly attenuate the chronic liver injury and fibrosis by restoring the anti-oxidative enzyme SOD activity in CCl4-, bile duct ligation- and alcohol-induced liver injury and fibrosis model. Recovery of SOD activity prevents the hepatocytes from apoptosis by inhibiting the oxidative stress-induced Erk1/2 signaling activation. The prevention of berberine and Coptis on chronic liver injury and fibrosis may contribute to its preventive effect against HCC. Then we found that berberine (as representative to Coptis) could suppress the angiogenesis of HCC, in which berberine does not directly act on the blood vessel formation, but suppress the expression and secretion of pro-angiogenic factors VEGF in HCC cells, and Id-1 inhibition by berberine plays a central role in the suppression of HIF-1α/VEGF and NF-κB pathways. We also found that berberine could induce both apoptotic and autophagic cell death in HCC, and the mitochondria related-caspases activation confers the apoptosis while mTOR inhibition initiates autophagy in berberine treated- cells. We found that berberine could suppress the migration and invasion of HCC cells as well, and Rho-GTPases/ROCK signaling is the particular target in berberine’s anti-invasive action. Finally, to dig out some molecular events involved in berberine’s action on HCC, we studied critically the mechanism underlying berberine’s inhibition on Cyclin D1 in HCC. We found berberine may promote the IKKα-induced Cyclin D1 phosphorylation at T286, and this may initiate the ubiquitination-dependent proteasomal degradation of Cyclin D1 in berberine-treated HCC cells and contribute to berberine’s anti-HCC action. Critical clinical trials and OMICS techniques were planned to further our comprehensive study on Coptis and berberine’s effects on HCC. In all, we found that berberine targets on different stages and molecules and exerts preventive and curative potential against HCC. Our study sheds light on the clinical application of berberine in HCC treatment.