title: Repositioning of amprenavir as a novel extracellular signal-regulated kinase-2 inhibitor and apoptosis inducer in MCF-7 human breast cancer.
abstract: 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.
authors.affiliation: Nursing Department, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Wenchun
authors.initials: W
authors.lastname: Jiang
authors.affiliation: School of Life Sciences, Sichuan University, Chengdu, Sichuan 610065, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Nephropathy, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, P.R. China.
authors.forename: Tongyu
authors.initials: T
authors.lastname: Li
authors.affiliation: Center for Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Hailian
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Pediatrics, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Qi
authors.affiliation: School of Life Sciences, Sichuan University, Chengdu, Sichuan 610065, P.R. China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Li
authors.affiliation: Center for Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Sichuan University, Chengdu, Sichuan 610065, P.R. China.
authors.forename: Jinku
authors.initials: J
authors.lastname: Bao
authors.affiliation: Center for Nephropathy, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, P.R. China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Huang
authors.affiliation: Center for Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D002219:Carbamates / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058492:Drug Repositioning / Q000379:methods*; D005260:Female; D005663:Furans; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D034741:RNA, Small Interfering; D013449:Sulfonamides; C095108:amprenavir; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1