木香抑制肝癌細胞之遷徙與增生

Abstract

Hepatocellular carcinoma (HCC) is the second highest cancer death in Taiwan, and the main risk factors for the development of HCC include infection with hepatitis B virus (HBV), hepatitis C virus (HCV) and chronic alcohol consumption. Therefore, development of effective chemotherapies is crucial for treatment of HCC. In recent years, the use of Chinese Herbal Medicines (CHMs) has been an adjuvant therapy for cancers. In present study, Hep3B, a classic hepatic carcinoma cell line, were used to investigate the anti-tumor effects of four CHMs (Saussurea lappa , Dwu Hwo Jih Sheng Tang , Achyranthes bidentata Bl , Long Daan Shieh Gan Tang ). First, by MTT and migration assay, the comparison of IC50 cell cytotoxicity and IC50 cell migration values indicated that Saussurea lappa (SL) has a higher inhibitory effect on the migration, but low cytotoxicity of Hep3B cells. Therefore, SL was chosen for further study. SL inhibits the migration of Hep3B cells with a medium inhibitory concentration (IC50 cell migration) value thirty-seven times lower than that of proliferation activity (IC50 cell cytotoxicity). In vivo efficacy was determined in a subcutaneous xenograft tumor model, NOD/SCID mice. Daily oral administration with SL at 2.25 g/kg inhibited the growth of tumor xenografts and lung metastases in NOD-SCID mice These results strongly suggest that SL has the inhibitory effect on cancer progression both in vitro and in vivo. And then, the anti-tumor molecular mechanisms of SL were further investigated. First, SL inhibited the cell migration and proliferation of Hep3B cells by inhibiting C/EBP regulates to the promoter region of VEGFR2, VEGFR3 and TGFßR1. Furthermore, the down-regulation of these receptors blocked the activation of Src, and decreased the translocation of ß-Catenin from cytosol to nuclear. In addition, SL inhibited the transcriptional activity of ß-Catenin leading to the suppression of Slug, fibronectin and N-cadherin expressions. SL also up-regulated E-cadherin which was negative regulated by Slug and Snail. Moreover, the organization of actin cytoskeleton, a key regulator for cell migration, was inhibited by SL. The regulation of actin cytoskeleton was through the modulation of the activity of small GTPase family including Rac1, Cdc42 and Rho A. Our results suggest that SL not only inhibits the migration of Hep3B cells through inhibiting the phosphorylation of Src, but also suppresses the activation of Cdc42, and then decreases the motility of Hep3B cells. In conclusion, present study provides a therapeutic rationale for the inhibitory effects of SL on HCC, and SL may be a potential antitumor therapeutic agent as an alternative medicine for controlling tumor growth and metastasis.