Abstract
Hepatocellular carcinoma (HCC) ranks as the fifth commonest of malignant tumors worldwide and the third leading cause of cancer-related death. Sorafenib is the first and only FDA-approved multi-kinase inhibitor for the treatment of advanced HCC in 2007, so screening the new drugs for treating HCC is important and urgent. Previously we had established zebrafish HCC models which developed HCC at 11 months. The first part of my thesis was to develop a HCC model which has higher incident and earlier onset. By using diet-induced obesity model, we found HBx and src in the background of p53 mutant triple transgenic female fish could develop HCC at 5 months of stage. This animal model will be used for screening drugs of anti-HCC. The second part of my thesis was using fli1:EGFP transgenic zebrafish embryos to screen the 560 derivatives of two LIB1F and LIB1O core structures which exhibited anti-angiogenesis effect, and discovered 69 derivatives exhibited anti-angiogenesis effect. Six compounds which did not result in embryo development defect was used for titration to determine their IC50. Two compounds (LIB1O0078 and LIB1O0144) were found having the lowest IC50, and were continued to test their therapeutic effect against liver cancer using transgenic fish, and anti-proliferation and anti-migration ability using xenotransplantation model and their toxicity. In xenotransplantation assay, LIB1O0078 exhibited better anti-proliferation ability and LIB1O0144 with better anti-migration ability. Using the 5 month old HBx and src in the background of p53 mutant triple transgenic female fish, orbital injection of drugs into blood for 4 weeks, we discovered LIB1O0078 could reverse HCC into normal. The therapeutic effect of LIB1O0144 was lesser than LIB1O0078. In terms of toxicity, LIB1O0078 and LIB1O0144 had lower hepatoxicity than sorafenib. In the survival test, LIB1O0078 and sorafenib had similar and less toxicity than LIB1O0144. From my thesis project, we discovered two novel small molecules which had therapeutic effect on HCC formation and were safer than FDA approved anti-liver cancer drug (sorafenib). Therefore, our data proved that the zebrafish platform was an excellent model for identification of new anti-cancer drugs.