SL1122-37, a novel derivative of sorafenib, has greater effects than sorafenib on the inhibition of human hepatocellular carcinoma (HCC) growth and prevention of angiogenesis.

ABSTRACT

SL1122-37 is a novel derivative of sorafenib that was characterized by introducing trifluoromethyl on the 4-position of indazole. We aimed to evaluate the effects of SL1122- 37 on human hepatocellular carcinoma (HCC) growth and on umbilical vein vascular endothelial cells (HUVECs) angiogenesis. Its efficacy and mechanisms were compared with sorafenib. SL1122-37 significantly prevented PLC/PRF/5 cell proliferation as estimated by colorimetric assay. Flow cytometry analysis showed the induction of apoptosis and arrest of cell cycle in G1 phase. Western blotting showed the decrease of cyclin D1 and regulation of apoptotic proteins. Further analysis suggested that these effects of SL1122-37 might arise from its roles in the inhibition of multi-kinases, including c-Kit and its downstream targets and the Wnt/ß-catenin pathway in PLC/PRF/5 cells. SL1122-37 also possessed the activity of antiangiogenesis, showing the prevention of HUVEC migration and capillary tube formation. Western blotting indicated the inhibition of VEGF and phosphorylation of VEGFR-2 in HUVECs. Statistical analysis suggested that SL1122-37 might possess greater activities than sorafenib in the prevention of HCC proliferation and HUVEC angiogenesis. Conclusion, SL1122-37 could develop as a potent anticancer agent for the treatment of HCC.