Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer

doi:10.1016/j.canlet.2013.08.046

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	Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer
	Li, Xian; Tong, Lin-Jiang; Ding, Jian; Meng, Ling-Hua
刊名	CANCER LETTERS
	2014
卷号	342 期号:1 页码:159-166
关键词	Combination Rapamycin Sunitinib Non-small cell lung cancer
ISSN号	0304-3835
DOI	10.1016/j.canlet.2013.08.046
文献子类	Article
英文摘要	Mammalian target of rapamycin (mTOR) acts as a hub integrating signals from nutrient availability and growth factors and plays central roles in regulating protein synthesis and cell growth, which has been validated as a promising target for cancer therapy. Rapamycin and its analogues have emerged as the first generation of mTOR inhibitors, but their efficacy is modest in clinical settings. Combinatorial use of rapamycin with other drugs is a promising strategy to improve its anticancer activity. Here we developed an unbiased systematic binary screening platform aiming to discover new remedy for rapamycin-based cancer therapy. We found that sunitinib emerged as one of the clinically available anticancer drugs screened that displayed significant synergy with rapamycin in NSCLC cells. Combination of rapamycin with sunitinib resulted in enhanced cell cycle arrest in G1 phase, which was accompanied with enhanced suppression of mTOR signaling and disruption of the negative feedback loop that activate AKT upon mTORC1 inhibition. Furthermore, sunitinib and rapamycin displayed synergistic activity against tube formation by human microvessel endothelial cells as well as outgrowth of endothelial tubes and microvessels both in vitro and in vivo, which is associated with down-regulation of VEGF secretion and HIF1 alpha expression. Our study demonstrated that new combinatorial regimen could be identified via systematic drug combination screening and established a mechanistic rationale for a combination approach using rapalogs and sunitinib in the treatment of human NSCLC. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
资助项目	National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301-001] ; National Natural Science Foundation of China[81021062] ; National Natural Science Foundation of China[81173079] ; Chinese Academy of Sciences[KSCX2-EW-Q-3]
WOS关键词	PRECLINICAL TESTING PROGRAM ; RENAL-CELL CARCINOMA ; GROWTH ; MTOR ; INHIBITION ; EFFICACY ; EVEROLIMUS ; AGENTS ; MODEL ; COLON
WOS研究方向	Oncology
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000328591100018
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277326]
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	Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Xian,Tong, Lin-Jiang,Ding, Jian,et al. Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer[J]. CANCER LETTERS,2014,342(1):159-166.
APA	Li, Xian,Tong, Lin-Jiang,Ding, Jian,&Meng, Ling-Hua.(2014).Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer.CANCER LETTERS,342(1),159-166.
MLA	Li, Xian,et al."Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer".CANCER LETTERS 342.1(2014):159-166.