Plumbagin restrains hepatocellular carcinoma angiogenesis by suppressing the migration and invasion of tumor-derived vascular endothelial cells

// YanFei Wei 1, * , Qi Yang 2, * , Yuan Zhang 3, * , TieJian Zhao 1 , XueMei Liu 1 , Jing Zhong 1 , Jing Ma 1 , YongXin Chen 1 , Chuan Zhao 1 , JunXuan Li 1 1 Department of Physiology, Faculty of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530200, China 2 Department of Emergency, Tianjin Fifth Central Hospital, Binhai New Area, Tianjin 300450, China 3 Department of State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 710032, China * These authors contributed equally to this work Correspondence to: Yan-Fei Wei, email: weiyanfei@163.com Keywords: plumbagin, HCC, angiogenesis, vascular endothelial cells, PI3K/AKT Received: July 02, 2016 Accepted: January 10, 2017 Published: January 20, 2017 ABSTRACT Tumor occurrence and development are very complicated processes. In addition to the roles of exogenous carcinogenic factors, the body’s internal factors also play important roles. These factors include the host response to the tumor and the tumor effect on the host. In particular, the proliferation, migration and activation of endothelial cells are involved in tumor angiogenesis. Angiogenesis is one of the hallmarks of cancer. In this study, we investigate whether plumbagin can abrogate angiogenesis-mediated tumor growth in hepatocellular carcinoma (HCC) and, if so, through which molecular mechanisms. We observed that in co-cultures of the human endothelial cell line EA.hy926 and the human hepatoma cell line SMMC-7721 and Hep3B, the hepatoma cells induced migration, invasion, tube formation and viability of the EA.hy926 cells in vitro , and these processes were inhibited by plumbagin. Real-Time PCR, Western Blot and Immunofluorescence staining showed that plumbagin treatment suppressed expression of angiogenesis pathways (PI3K-Akt, VEGF/KDR and Angiopoietins/Tie2) and angiogenic factors (VEGF, CTGF, ET-1, bFGF),which is associated with tumor angiogenesis in cancer cells and xenograft tumor tissues. Furthermore, plumbagin was also found to significantly reduce tumor growth in an orthotopic HCC mouse model and to inhibit tumor-induced angiogenesis in HCC patient xenografts. Taken together, our findings strongly suggest that plumbagin might be a promising anti-angiogenic drug with significant antitumor activity in HCC.