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Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death

文献类型：期刊论文

作者Ouchida, Amanda Tomie2; Li, Yingbo2; Geng, Jiefei2; Najafov, Ayaz1,2; Ofengeim, Dimitry2; Sun, Xiaoxiao3; Yu, Qiang3; Yuan, Junying1,2
刊名CELL DEATH & DISEASE
出版日期2018-01-26
卷号9
ISSN号2041-4889
DOI10.1038/s41419-017-0170-9
文献子类Article
英文摘要Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anticancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy. We identified that TAK-165, a HER2 inhibitor, even when used at low nanomolar doses in combination with AC220, was able to induce cell death in different cancer cells, but not in non-cancer cell lines. We showed that TAK-165 and AC220 act synergistically to downregulate key signaling pathways and potently induce cancer cell death. Furthermore, we demonstrated that TAK-165 inhibited autophagy in a HER2-independent manner. Finally, we showed that the combination of TAK-165 and AC220 induced cell death in cancer cells through the activation of chaperone-mediated autophagy. Overall, these findings support the strategy for using AC220 and an autophagy inhibitor such as TAK-165 in a combinatorial treatment to enhance the efficacy of cancer therapies.
WOS关键词CHAPERONE-MEDIATED AUTOPHAGY ; DRUG-RESISTANCE ; LUNG-CANCER ; THERAPY ; DEGRADATION ; MECHANISMS ; LEUKEMIA ; HER2 ; 3-METHYLADENINE ; PROLIFERATION
资助项目Ludwig Cancer Center at Harvard Medical School[00000000] ; Chinese Academy of Sciences[00000000] ; CNPq[208301/2014-3]
WOS研究方向Cell Biology
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000427388100017
源URL[http://119.78.100.183/handle/2S10ELR8/279944]  
专题药理学第一研究室
通讯作者Yuan, Junying
作者单位1.Harvard Med Sch, Ludwig Canc Ctr, Boston, MA 02115 USA;
2.Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA;
3.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Ouchida, Amanda Tomie,Li, Yingbo,Geng, Jiefei,et al. Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death[J]. CELL DEATH & DISEASE,2018,9.
APA Ouchida, Amanda Tomie.,Li, Yingbo.,Geng, Jiefei.,Najafov, Ayaz.,Ofengeim, Dimitry.,...&Yuan, Junying.(2018).Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death.CELL DEATH & DISEASE,9.
MLA Ouchida, Amanda Tomie,et al."Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death".CELL DEATH & DISEASE 9(2018).

入库方式： OAI收割

来源：上海药物研究所

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