Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a.

Abstract

The pharmacokinetic (PK) and potential effects of Emodin on liver cancer were systematically evaluated in this study. Both the intragastric administration (i.g.) and hypodermic injection (i.h.) of Emodin exhibited a strong absorption (absorption rate < 1h) and elimination capacity (t1/2 ≈ 2h). The tissue distribution of Emodin after i.h. was rapid and wide. The stability of Emodin in three species of liver microsomes wasrat >human> beagle dog. These PK data provided the basis for the subsequent animal experiments. In liver cancer patient tissues, the expression of vascular endothelial growth factor (VEGF)-induced signaling pathways, including phosphorylated VEGF receptor 2 (VEGFR2), AKT, and ERK1/2,were simultaneously elevated, but miR-34a expression was reduced and negatively correlated with SMAD2 and SMAD4. Emodin inhibited the expression of SMAD2/4 in HepG2 cells by inducing the miR-34a level. Subsequently, BALB/c nude mice received a daily subcutaneous injection of HepG2 cells with or without Emodin treatment (1mg/kg or 10mg/kg), and Emodin inhibited tumorigenesis and reduced the mortality rate in a dose-dependent manner. In vivo experiments showed that cell proliferation, migration, and invasion were promoted by VEGF or miR-34a signal treatment but were inhibited when combined with Emodin treatment. All these results demonstrated that Emodin inhibited tumorigenesis in liver cancer by simultaneously inhibiting the VEGFR2-AKT-ERK1/2signaling pathway and promoting a miR-34a-mediated signaling pathway.