Repositioning of amprenavir as a novel extracellular signal-regulated kinase-2 inhibitor and apoptosis inducer in MCF-7 human breast cancer
| Autor: | Jie Chen, Jinku Bao, Hailian Wang, Ping Qi, Tongyu Li, Wei Shi, Yi Wang, Wenchun Jiang, Xin Li, Guodong Huang, Chunyang Li |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Cell Survival Mice Nude Antineoplastic Agents Apoptosis Breast Neoplasms Molecular Dynamics Simulation Biology Mice 03 medical and health sciences Amprenavir 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans Phosphorylation RNA Small Interfering Kinase activity Furans Cell Proliferation Mitogen-Activated Protein Kinase 1 Sulfonamides Bcl-2-Like Protein 11 Kinase Drug Repositioning HIV Protease Inhibitors Cell cycle Xenograft Model Antitumor Assays Mice Inbred C57BL Molecular Docking Simulation Drug repositioning 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research Female RNA Interference Carbamates Signal transduction Signal Transduction medicine.drug |
| Zdroj: | International Journal of Oncology. 50:823-834 |
| ISSN: | 1791-2423 1019-6439 |
| Popis: | Computational drug repositioning by virtually screening existing drugs for additional therapeutic usage could efficiently accelerate anticancer drug discovery. Herein, a library of 1447 Food and Drug Administration (FDA)-approved small molecule drugs was screened in silico for inhibitors of extracellular signal-regulated kinase 2 (ERK2). Then, in vitro kinase assay demonstrated amprenavir, a HIV-1 protease inhibitor, as a potential kinase inhibitor of ERK2. The in vivo kinase assay indicated that amprenavir could inhibit ERK2-mediated phosphorylation of BimEL at Ser69. Amprenavir could suppress this phosphorylation in MCF-7 cells, which may further facilitate the association of BimEL with several pro-survival molecules. Additionally, inhibition of ERK2-BimEL signaling pathway by amprenavir could contribute to its anti-proliferative and apoptosis-inducing activity in MCF-7 cells. Finally, in vivo tumor growth and immunohistochemical studies confirmed that amprenavir remarkably suppressed tumor proliferation and induce apoptosis in MCF-7 xenografts. Taken together, amprenavir can effectively inhibit the kinase activity of ERK2, and thus induces apoptosis and inhibits tumor growth in human MCF-7 cancer cells both in vitro and in vivo, making amprenavir a promising candidate for future anticancer therapeutics. |
| Databáze: | OpenAIRE |
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