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Tumour Biol. 2016 Sep;37(9):12791-12803. Epub 2016 Jul 23.

Evodiamine exerts anti-tumor effects against hepatocellular carcinoma through inhibiting β-catenin-mediated angiogenesis.

Shi L1,2,3, Yang F3, Luo F1,2, Liu Y1,2, Zhang F3, Zou M4, Liu Q5,6.

Author information

1
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
2
The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
3
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, China.
4
Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 210029, China.
5
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. drqzliu@hotmail.com.
6
The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. drqzliu@hotmail.com.

Abstract

Hepatocellular carcinoma (HCC) is a highly vascular tumor with high microvessel density and high levels of circulating vascular endothelial growth factor (VEGF). Thus, the angiogenesis pathway is an attractive therapeutic target for HCC. The anti-tumor effects of evodiamine, a quinolone alkaloid isolated from Euodia rutaecarpa (Juss.) Benth. (Rutaceae), were investigated in a mouse xenograft model using BALB/c nude mice, various HCC cell lines (HepG2, SMMC-7721, H22), and human umbilical vein endothelial cells (HUVECs). The effects of evodiamine on tumor volumes and weights, levels of tumor markers, angiogenesis in vivo and in vitro, cell viability, and cell migration and invasion were measured, and the mechanism through which its effects are achieved was investigated. Transcriptional regulation of VEGFa via interaction with β-catenin was established by luciferase activity assays and electrophoretic mobility shift assays. In a subcutaneous H22 xenograft model, evodiamine inhibited tumor growth and reduced serum tumor markers and the levels of β-catenin and VEGFa. It also blocked VEGF-induced angiogenesis in a Matrigel plug assay. Evodiamine suppressed cellular proliferation, invasion, and migration and inhibited tube formation of HUVECs. Moreover, in a concentration-dependent manner, evodiamine reduced the number of capillary sprouts from Matrigel-embedded rat thoracic aortic rings. Also, evodiamine suppressed various biomarkers of angiogenesis and the expression of β-catenin. Evodiamine decreased β-catenin levels activated by LiCl, which led to reduced expression of VEGFa. In addition, β-catenin interacted with VEGFa and transcriptionally regulated VEGFa, an effect inhibited by evodiamine in HCCs. Moreover, in an SMMC-7721 xenograft model, evodiamine suppressed tumor growth, various biomarkers of angiogenesis, and the levels of β-catenin and VEGFa. Evodiamine has anti-tumor effects on HCCs through inhibiting β-catenin, which interacts with and reduces VEGFa expression, thus inhibiting angiogenesis. These results indicate that evodiamine, which inhibits cellular invasion and migration and blocks angiogenesis, is a potential therapeutic agent for HCCs.

KEYWORDS:

Angiogenesis; Evodiamine; Hepatocellular carcinoma; Vascular endothelial growth factor; β-Catenin

PMID:
27449032
DOI:
10.1007/s13277-016-5251-3
[Indexed for MEDLINE]

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