Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR(2) and miR-34a

摘要

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 < 1 h) and elimination capacity (t(1/2) approximate to 2 h). 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 (VEGFR(2)), AKT, and ERK1/2,were simultaneously elevated, but miR-34a expression was reduced and negatively correlated with SMAD(2) and SMAD(4). Emodin inhibited the expression of SMAD(2/4) 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 (1 mg/kg or 10 mg/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 VEGFR(2)-AKT-ERK(1/2)signaling pathway and promoting a miR-34a-mediated signaling pathway.