Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy
| العنوان: | Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy |
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| المؤلفون: | Michael A. Hollingsworth, Jared Baxter, Sandeep Rana, Caroline M. Robb, Yogesh A. Sonawane, Smit Kour, Ayrianne J. Crawford, Xu Luo, Smitha Kizhake, Jacob I. Contreras, Amarnath Natarajan, Hannah M. King |
| المصدر: | ACS Chemical Biology. 13:1148-1152 |
| بيانات النشر: | American Chemical Society (ACS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Cell, Caspase 3, Biochemistry, Article, 03 medical and health sciences, 0302 clinical medicine, Cyclin-dependent kinase, Cell Line, Tumor, Neoplasms, medicine, Humans, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, biology, Chemistry, Kinase, General Medicine, High-Throughput Screening Assays, 030104 developmental biology, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Cell culture, Apoptosis, Doxycycline, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Molecular Medicine, Drug Therapy, Combination, Apoptosis Regulatory Proteins, Genetic screen |
| الوصف: | The study presented here provides a framework for the discovery of unique inhibitor combinations that target the apoptosis network for cancer therapy. A pair of doxycycline (Dox) -inducible cell lines that specifically report on the ability of an inhibitor to induce apoptosis either by targeting the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm were used. Cell-based assays were optimized for high throughput screening (HTS) with caspase 3/7 as a read out. HTS with a 355-member kinase inhibitor library and the panel of Dox-inducible cell lines revealed that cyclin dependent kinase (CDK) inhibitors induced apoptosis by targeting the Mcl-1 arm whereas PI3K inhibitors induced apoptosis by targeting the Bcl-2/Bcl-xL/Bcl-w arm. Validation studies identified unique combinations that synergistically inhibited growth and induced apoptosis in a panel of cancer cell lines. Since these inhibitors have been or are currently in clinical trials as single agents, the combinations can be rapidly translated to the clinics. |
| تدمد: | 1554-8937 1554-8929 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::51e0dc76e46b8207e6cf81454345398a https://doi.org/10.1021/acschembio.8b00077 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....51e0dc76e46b8207e6cf81454345398a |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15548937 15548929 |
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