中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer

文献类型:期刊论文

作者Li, Xian; Tong, Lin-Jiang; Ding, Jian; Meng, Ling-Hua
刊名CANCER LETTERS
出版日期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
DOI10.1016/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.
WOS关键词PRECLINICAL TESTING PROGRAM ; RENAL-CELL CARCINOMA ; GROWTH ; MTOR ; INHIBITION ; EFFICACY ; EVEROLIMUS ; AGENTS ; MODEL ; COLON
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研究方向Oncology
语种英语
WOS记录号WOS:000328591100018
出版者ELSEVIER IRELAND LTD
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.

入库方式: OAI收割

来源:上海药物研究所

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