X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response
文献类型：期刊论文
| 作者 | Zhao, Zhixin; Zhu, Jianming; Quan, Haitian ; Wang, Guimin; Li, Bo; Zhu, Weiliang; Xie, Chengying; Lou, Liguang
|
| 刊名 | ONCOTARGET
 |
| 出版日期 | 2016-05-17 |
| 卷号 | 7期号:20页码:29648-29663 |
| 关键词 | X66 HSP90 HSF-1 heat shock response celastrol |
| ISSN号 | 1949-2553 |
| DOI | 10.18632/oncotarget.8818 |
| 文献子类 | Article |
| 英文摘要 | Heat shock protein 90 (HSP90) is essential for cancer cells to assist the function of various oncoproteins, and it has been recognized as a promising target in cancer therapy. Although the HSP90 inhibitors in clinical trials have shown encouraging clinical efficacy, these agents induce heat shock response (HSR), which undermines their therapeutic effects. In this report, we detailed the pharmacologic properties of 4-(2-((1H-indol-3-yl)methylene)hydrazinyl)-N-(4-bromophenyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2-amine (X66), a novel and potent HSP90 inhibitor. X66 binds to the N-terminal domain in a different manner from the classic HSP90 inhibitors. Cellular study showed that X66 depleted HSP90 client proteins, resulted in cell cycle arrest and apoptosis, and inhibition of proliferation in cancer cell lines. X66 did not activate heat shock factor-1 (HSF-1) or stimulate transcription of HSPs. Moreover, the combination of X66 with HSP90 and proteasome inhibitors yielded synergistic cytotoxicity which was involved in X66-mediated abrogation of HSR through inhibition of HSF-1 activity. The intraperitoneal administration of X66 alone depleted client protein and inhibited tumor growth, and led to enhanced activity when combined with celastrol as compared to either agent alone in BT-474 xenograft model. Collectively, the HSP90 inhibitory action and the potent antitumor activity, with the anti-HSR action, promise X66 a novel HSP90-targeted agent, which merits further research and development. |
| WOS关键词 | HSP90 MOLECULAR CHAPERONE ; TRANSCRIPTION FACTOR HSF1 ; CANCER-CELLS ; STRESS ; ACTIVATION ; RESISTANCE ; APOPTOSIS ; COMPLEX ; BINDING ; HEAT-SHOCK-PROTEIN-27 |
| 资助项目 | National Natural Science Foundation of China[81273546] ; Shanghai Science and Technology Committee[14DZ2294100] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09102008] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX094021 02-001] |
| WOS研究方向 | Oncology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000377742600070 |
| 出版者 | IMPACT JOURNALS LLC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276042]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Xie, Chengying; Lou, Liguang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Zhixin,Zhu, Jianming,Quan, Haitian,et al. X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response[J]. ONCOTARGET,2016,7(20):29648-29663. |
| APA | Zhao, Zhixin.,Zhu, Jianming.,Quan, Haitian.,Wang, Guimin.,Li, Bo.,...&Lou, Liguang.(2016).X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response.ONCOTARGET,7(20),29648-29663. |
| MLA | Zhao, Zhixin,et al."X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response".ONCOTARGET 7.20(2016):29648-29663. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。