Anti-angiogenic and vascular disrupting effects of C9, a new microtubule-depolymerizing agent

doi:10.1111/j.1476-5381.2009.00112.x

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Anti-angiogenic and vascular disrupting effects of C9, a new microtubule-depolymerizing agent
	Ren, Xuan 2; Dai, Mei 2; Lin, Li-Ping 2; Li, Pui-Kai 1; Ding, Jian2
刊名	BRITISH JOURNAL OF PHARMACOLOGY
	2009-04
卷号	156 期号:8 页码:1228-1238
关键词	C9 anti-angiogenesis vascular disrupting effect microtubule Raf-MEK-ERK signalling pathway
ISSN号	0007-1188
DOI	10.1111/j.1476-5381.2009.00112.x
文献子类	Article
英文摘要	The critical role of blood supply in the growth of solid tumours makes blood vessels an ideal target for anti-tumour drug discovery. The anti-angiogenic and vascular disrupting activities of C9, a newly synthesized microtubule-depolymerizing agent, were investigated with several in vitro and in vivo models. Possible mechanisms involved in its activity were also assessed. Microtubule-depolymerizing actions were assessed by surface plasmon resonance binding, competitive inhibition and cytoskeleton immunofluorescence. Anti-angiogenic and vascular disrupting activities were tested on proliferation, migration, tube formation with human umbilical vein endothelial cells, and in rat aortic ring, chick chorioallantoic membrane and Matrigel plug assays. Western blots and Rho activation assays were employed to examine the role of Raf-MEK-ERK (mitogen-activated ERK kinase, extracellular signal-regulated kinase) and Rho/Rho kinase signalling. C9 inhibited proliferation, migration and tube formation of endothelial cells and inhibited angiogenesis in aortic ring and chick chorioallantoic membrane assays. C9 induced disassembly of microtubules in endothelial cells and down-regulated Raf-MEK-ERK signalling activated by pro-angiogenic factors. In addition, C9 disrupted capillary-like networks and newly formed vessels in vitro and rapidly decreased perfusion of neovasculature in vivo. Endothelial cell contraction and membrane blebbing induced by C9 in neovasculature was dependent on the Rho/Rho kinase pathway. Anti-angiogenic and vascular disruption by C9 was associated with changes in morphology and function of endothelial cells, involving the Raf-MEK-ERK and Rho/Rho kinase signalling pathways. These findings strongly suggest that C9 is a new microtubule-binding agent that could effectively target tumour vasculature.
资助项目	National Natural Science Foundation of China[30572201] ; National Natural Science Foundation of China[30721005] ; National Natural Science Foundation of China[30730103]
WOS关键词	CONFORMATIONALLY RESTRICTED ANALOGS ; HUMAN ENDOTHELIAL-CELLS ; SIGNAL-TRANSDUCTION ; TARGETING ACTIVITY ; TUBE FORMATION ; IN-VIVO ; TUBULIN ; BINDING ; CANCER ; GROWTH
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000265008100007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279271]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ding, Jian
作者单位	1.Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA 2.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Ren, Xuan,Dai, Mei,Lin, Li-Ping,et al. Anti-angiogenic and vascular disrupting effects of C9, a new microtubule-depolymerizing agent[J]. BRITISH JOURNAL OF PHARMACOLOGY,2009,156(8):1228-1238.
APA	Ren, Xuan,Dai, Mei,Lin, Li-Ping,Li, Pui-Kai,&Ding, Jian.(2009).Anti-angiogenic and vascular disrupting effects of C9, a new microtubule-depolymerizing agent.BRITISH JOURNAL OF PHARMACOLOGY,156(8),1228-1238.
MLA	Ren, Xuan,et al."Anti-angiogenic and vascular disrupting effects of C9, a new microtubule-depolymerizing agent".BRITISH JOURNAL OF PHARMACOLOGY 156.8(2009):1228-1238.