Antiangiogenesis effect of timosaponin AⅢ on HUVECs in vitro and zebrafish embryos in vivo  

作　　者：Zhong-yan Zhou Wai-rong Zhao Ying Xiao Xiang-ming Zhou Chen Huang Wen-ting Shi Jing Zhang Qing Ye Xin-lin Chen Jing-yi Tang 

机构地区：[1]Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200032,China [2]State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences,University of Macao,Macao,China [3]Cardiac rehabilitation Center of Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200032,China

出　　处：《Acta Pharmacologica Sinica》2020年第2期260-269,共10页中国药理学报（英文版）

基　　金：the Shanghai University of Traditional Chinese Medicine(Al-U17205010301);the National Health Commission of Shanghai(GWIV-28,ZY-(2018-2020)-FWTX-8001);the National Natural Science Foundation of China(81603549,81673726,and 81760860)。

摘　　要：Timosaponin AIII(Timo AIII)is a natural steroidal saponin isolated from the traditional Chinese herb Anemarrhena asphodeloides Bge with proved effectiveness in the treatment of numerous cancers.However,whether Timo AIII suppresses tumor angiogenesis remains unclear.In the present study,we investigated the antiangiogenesis effects of Timo AIII and the underlying mechanisms in human umbilical vein endothelial cells(HUVECs)in vitro and zebrafish embryos in vivo.We showed that treatment with Timo AIII(0.5–2μM)partially disrupted the intersegmental vessels(ISVs)and subintestinal vessels(SIVs)growth in transgenic zebrafish Tg(fli-1a:EGFP)y1.Timo AIII(0.5–4μM)dose-dependently inhibited VEGF-induced proliferation,migration,invasion,and tube formation of HUVECs,but these inhibitory effects were not due to its cytotoxicity.We further demonstrated that Timo AIII treatment significantly suppressed the expression of VEGF receptor(VEGFR)and the phosphorylation of Akt,MEK1/2,and ERK1/2 in HUVECs.Timo AIII treatment also significantly inhibited VEGF-triggered phosphorylation of VEGFR2,Akt,and ERK1/2 in HUVECs.Moreover,we conducted RNA-Seq and analyzed the transcriptome changes in both HUVECs and zebrafish embryos following Timo AIII treatment.The coexpression network analysis results showed that various biological processes and signaling pathways were enriched including angiogenesis,cell motility,cell adhesion,protein serine/threonine kinase activity,transmembrane signaling receptor activity,growth factor activity,etc.,which was consistent with the antiangiogenesis effects of Timo AIII in HUVECs and zebrafish embryos.We conclude that the antiangiogenesis effect of Timo AIII is mediated through VEGF/PI3K/Akt/MAPK signaling cascade;Timo AIII potentially exerts antiangiogenesis effect in cancer treatment.

关 键 词：TIMOSAPONIN AIII Traditional Chinese HERBAL NEOVASCULARIZATION NEOPLASM VEGF/PI3K/Akt/MAPK Transcriptome Zebrafish HUVECS SU5416 

分 类 号：R96[医药卫生—药理学]