DCZ5248, a novel dual inhibitor of Hsp90 and autophagy, exerts antitumor activity against colon cancer
文献类型：期刊论文
| 作者 | Chen, Xiang-ling1,2; Liu, Peng2; Zhu, Wei-liang1,2 ; Lou, Li-guang1,2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2020-05-13 |
| 页码 | 10 |
| 关键词 | DCZ5248 Hsp90 autophagy lysosomal function antitumor activity colon cancer |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-020-0398-2 |
| 通讯作者 | Lou, Li-guang(lglou@mail.shcnc.ac.cn) |
| 英文摘要 | Hsp90 is a potential therapeutic target for tumor, as it maintains the stability of a variety of proteins related to tumor development and progression. Autophagy is a self-degradation process to maintain cellular homeostasis and autophagy inhibitors can suppress tumor growth. In this study, we identified DCZ5248, a triazine derivative, was a dual inhibitor of both Hsp90 and late-autophagy with potent antitumor activity against colon cancer cells in vitro and in vivo. We showed that DCZ5248 (0.1-10 mu M) induced dose-dependent degradation of Hsp90 client proteins (AKT, CDK4, CDK6 and RAF-1) in HCT 116 colon cancer cells through a proteasome-dependent pathway. Meanwhile, DCZ5248 (0.3 mu M) induced cytoplasmic vacuole formation, LC3 II conversion, p62 protein upregulation, and inhibited autophagy at the late stage in the colon cancer cell lines tested. We further revealed that the inhibition of autophagy was achieved by impairing lysosomal functions through induction of lysosomal acidification and attenuation of lysosomal cathepsin activity. The modulation of autophagy by DCZ5248 was independent of Hsp90 inhibition as the autophagy inhibition was not blocked by Hsp90 knockdown. Importantly, inhibition of both Hsp90 function and autophagy by DCZ5248 induced G(1)-phase cell cycle arrest, apoptosis, and exerted potent antitumor activity against colon cancer cells both in vitro and in vivo. These findings demonstrate that DCZ5248 is a novel dual inhibitor of Hsp90 and autophagy with potential for colon cancer therapy. |
| WOS关键词 | PROTEIN 90 INHIBITORS ; ADVANCED SOLID TUMORS ; PHASE-I TRIAL ; INDUCED APOPTOSIS ; RESISTANCE ; MUTANT ; HYDROXYCHLOROQUINE ; DEGRADATION ; GANETESPIB ; TEMOZOLOMIDE |
| 资助项目 | National Natural Science Foundation of China[81273546] ; Science and Technology Commission of Shanghai Municipality[18DZ2293200] ; Yunnan Province Sciences and Technology plan[2017ZF010] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000532622200003 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/280356]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Lou, Li-guang |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Xiang-ling,Liu, Peng,Zhu, Wei-liang,et al. DCZ5248, a novel dual inhibitor of Hsp90 and autophagy, exerts antitumor activity against colon cancer[J]. ACTA PHARMACOLOGICA SINICA,2020:10. |
| APA | Chen, Xiang-ling,Liu, Peng,Zhu, Wei-liang,&Lou, Li-guang.(2020).DCZ5248, a novel dual inhibitor of Hsp90 and autophagy, exerts antitumor activity against colon cancer.ACTA PHARMACOLOGICA SINICA,10. |
| MLA | Chen, Xiang-ling,et al."DCZ5248, a novel dual inhibitor of Hsp90 and autophagy, exerts antitumor activity against colon cancer".ACTA PHARMACOLOGICA SINICA (2020):10. |
入库方式： OAI收割
来源：上海药物研究所
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