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 |
| 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. |
| 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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