title: Evodiamine exerts anti-tumor effects against hepatocellular carcinoma through inhibiting β-catenin-mediated angiogenesis.
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.
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.|School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, China.
authors.forename: Le
authors.initials: L
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Luo
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 210029, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zou
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. drqzliu@hotmail.com.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. drqzliu@hotmail.com.
authors.forename: Qizhan
authors.initials: Q
authors.lastname: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D032086:Evodia / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010936:Plant Extracts; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C049639:evodiamine
keywords: Angiogenesis; Evodiamine; Hepatocellular carcinoma; Vascular endothelial growth factor; β-Catenin