标题：Inhibition of angiogenesis involves in anticancer activity of riccardin D, a macrocyclic bisbibenzyl, in human lung carcinoma
作者：Sun, Cui-cui; Zhang, Yu-sheng; Xue, Xia; Cheng, Yan-na; Liu, Hui-ping; Zhao, Cui-rong; Lou, Hong-xiang; Qu, Xian-jun
作者机构：[Sun, Cui-cui; Xue, Xia; Cheng, Yan-na; Liu, Hui-ping; Zhao, Cui-rong; Lou, Hong-xiang; Qu, Xian-jun] Shandong Univ, Sch Pharmaceut Sci, Dept Pharmaco 更多
通讯作者地址：[Qu, XJ]Shandong Univ, Sch Pharmaceut Sci, Dept Pharmacol, Jinan 250012, Shandong, Peoples R China.
来源：EUROPEAN JOURNAL OF PHARMACOLOGY
关键词：Macrocyclic bisbibenzyl; Riccardin D; Angiogenesis; Angiogenic factor;; Xenograft; Mean vascular density
摘要：Riccardin D is a novel macrocyclic bisbibenzyl compound extracted from Chinese liverwort plant Dumortiera hirsuta. Our previous studies showed that riccardin D is a DNA topo II inhibitor and has therapeutic potential for treatment of cancers. In this combined in vitro and in vivo study, we examined the inhibitory effects of riccardin Don tumor angiogenesis and the subsequent effect of anticancer activity was evaluated. Incubation with riccardin D weakly inhibited the proliferation of human umbilical vascular endothelial cells (HUVEC) as estimated by the 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide ( MTT) assay. The scratch wound experiment showed that riccardin D effectively decreased the motility and migration of HUVEC cells. Riccardin D inhibited the formation of capillary tube as demonstrated by decrease of branch points formed by HUVEC cells on 3-D Matrigel. We examined the levels of angiogenic factors including vascular endothelial growth factor (VEGF), VEGF receptor 2, epidermal growth factor receptor (EGF receptor), and matrix metalloproteinase (MMPs) in HUVEC cells. The expressions of VEGF, phospho-VEGF receptor 2, EGF receptor and MMP-2 were significantly reduced by riccardin D as estimated by Western blot assay and real-time quantitative PCR analysis. The decrease of VEGF was also detected in riccardin D-treated human lung cancer H460 cells. The anticancer activity of riccardin D was then evaluated in a mouse model in which riccardin D delayed the growth of H460 xenografts without obvious toxicity to animals after three weeks injection. To evaluate the role of antiangiogenesis of riccardin D in mice, CD34 immunohistochemical staining was employed to analyze the mean vascular density in H460 xenograft tissues. The number of blood vessels was significantly decreased after riccardin D treatment These results suggest that riccardin D display the inhibitory effect on growth of human lung carcinoma cells and that the inhibition of angiogenesis may involve in anticancer activity of riccardin D. (C) 2011 Elsevier B.V. All rights reserved.