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

• Published in: Investigational new drugs Vol. 38; no. 2; pp. 229 - 245
• Main Authors: Bai, Jianguo, Wu, Jianfei, Tang, Ruifeng, Sun, Chao, Ji, Junwei, Yin, Zhaolin, Ma, Guangjun, Yang, Wei
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2020; Springer Nature B.V
• Subjects: Absorption; AKT protein; Animal research; Anthraquinone; Cancer; Cell migration; Cell proliferation; Dosage; Emodin; Growth factors; Injection; Liver; Liver cancer; Medicine; Medicine & Public Health; Microsomes; Oncology; Pharmacology; Pharmacology/Toxicology; Preclinical Studies; Signal transduction; Signaling; Smad2 protein; Smad4 protein; Studies; Tissues; Tumorigenesis; Vascular endothelial growth factor; VEGFR2; Liver cancer; miR-34a
• ISSN: 0167-6997; 1573-0646; 1573-0646
• DOI: 10.1007/s10637-019-00777-5

Summary 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  ≈ 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 ERK 1/2 ,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.