Investigation and development of Graptopetalum paraguayense and its active components as anti-liver fibrotic and anti-liver cancer drugs

• Main Authors: Wei-Hsiang Hsu, 許偉祥
• Other Authors: Chi-Ying F. Huang
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/55956961946750233990

博士 === 國立陽明大學 === 生物藥學研究所 === 103 === Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death worldwide. Sorafenib is the only drug for patients with advanced-stage hepatocellular carcinoma (HCC) that has been shown to confer a survival benefit to patients with HCC; however, it has many side effects. Thus, alternate therapeutic strategies with improved safety and therapeutic efficacy for the management of HCC should be developed. This thesis focused on Graptopetalun paraguayenseas (GP) and its purifed fraction. To study the effect of GP on liver fibrosis and liver cancer. Extracts from GP down-regulated protein expression levels of several onco-proteins, including AURKA, AURKB and FLJ10540, in HCC cells. Furthermore, we used these proteins expression profile as a criterion and guidance for the isolation of active components from the GP and the designated fraction as HH-F3. The HH-F3, which was enriched with active ingredients, exhibited cytotoxic effects and suppressed the above mentioned oncoproteins expression in HCC cell. Mechanistic studies indicated that the HH-F3 induced apoptosis in HCC cells via the loss of mitochondrial membrane potential and ROS generation. HH-F3 also enhanced PTEN expression and decreased AKT phosphorylation at Ser473 at a dose-dependent manner in HCC cells. Moreover, GP/HH-F3 could suppress MAPK pathway in HCC and be a possible HDAC inhibitor. GP/HH-F3 also regulate host energy generation and lipogenesis machinery, which is regulated by AKT/AMPK/SIRT1/PGC1 pathway. Combination of GP/HH-F3 and sorafenib synergistically inhibits the proliferation of HCC cells and GP/HH-F3 could suppress sorafenib-resistant HCC growth via inhibition TGF-β pathway, ID proteins, SPAG5 and CRKL expression. In a diethylnitrosamine (DEN)-induced liver fibrosis and cancer rat treatment with GP extracts and the HH-F3 decreased hepatic collagen contents and inhibited tumor growth. In allograft mouse model (BNL injected subcutaneously), treatment with GP extracts and the HH-F3 inhibited tumor growth. In addition, HH-F3 could inhibit HBV replication and transcription. In summary, GP/HH-F3 can protect the liver by suppressing tumor growth via regulation PTEN/AKT, MAPK, HDAC, β-catenin, and AMPK pathways. Taken together, GP/HH-F3 could serve as potential drugs for treating chronic liver disease and HCC.