1118-20, an indazole diarylurea compound, inhibits hepatocellular carcinoma HepG2 proliferation and tumour angiogenesis involving Wnt/β-catenin pathway and receptor tyrosine kinases.

Abstract

Sorafenib is a first multi-kinase inhibitor and one of the most widely used small-molecule oral-targeted drugs. It has been widely used for the treatment of patients with advanced renal cell carcinoma and hepatocellular carcinoma. However, some common adverse effects of sorafenib may impact quality of life. In this study, we evaluated the inhibitory effect on the growth of hepatocellular carcinoma cell line (HepG2) and suppression on angiogenesis of 1118-20, a newly synthesized indazole diarylurea compound. We evaluated the activity of 1118-20 against HepG2 cells growth and tumour angiogenesis of human umbilical vascular endothelial cell line (HUVECs) with sorafenib as a positive control. The cytotoxic efficacy of 1118-20 was higher in HepG2 cells than human normal liver cell line (HL-7702). 1118-20 significantly suppressed the proliferation of HepG2 cells by apoptosis induction via Bcl-2 family-mediated mitochondria pathway and inhibition on Wnt/β-catenin signalling pathway. 1118-20 effectively blunt the motility and migration, and inhibited the formation of capillary tube of HUVECs through suppression of angiogenic factors expression. Moreover, the results indicated that 1118-20 exerted higher efficacy than sorafenib on tumour cell proliferation and angiogenesis. Compared with its parent drug sorafenib, we found that 1118-20 possessed more potential on inhibition of angiogenesis and cancer cells growth. Inhibitory effect of 1118-20 on non-tumour liver cell HL-7702 was lower than that on hepatoma carcinoma cell HepG2. These results suggest that 1118-20 is a promising candidate compound that could be developed to a potent anticancer agent.