title: Identification of a natural compound by cell-based screening that enhances interferon regulatory factor-1 activity and causes tumor suppression.
abstract: The transcription factor interferon regulatory factor-1 (IRF-1) is induced by many tumor-suppressive stimuli and can mediate antiproliferative and proapoptotic effects in cancer cells. Thus, identifying agents that enhance IRF-1 activity may be an effective approach to cancer therapy. A cell-based screening assay was developed to identify extracts and compounds that could enhance IRF-1 activity, using an IRF-1-dependent luciferase reporter cell line. Through this approach, we identified a natural product extract and a known active component of this extract, baicalein, which causes a marked increase in IRF-1-dependent reporter gene expression and IRF-1 protein, with modulation of known IRF-1 targets PUMA and cyclin D1. Baicalein causes suppression of growth in vitro in multiple cancer cell lines in the low micromolar range. IRF-1 plays a role in this growth suppression as shown by significant resistance to growth suppression in a breast cancer cell line stably transfected with short hairpin RNA against IRF-1. Finally, intraperitoneal administration of baicalein by repeated injection causes inhibition of growth in both xenogeneic and syngeneic mouse models of cancer without toxicity to the animals. These findings indicate that identifying enhancers of IRF-1 activity may have utility in anticancer therapies and that cell-based screening for activation of transcription factors can be a useful approach for drug discovery.
authors.affiliation: Department of Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Gao
authors.forename: Yujun
authors.initials: Y
authors.lastname: Wang
authors.forename: Quanhua
authors.initials: Q
authors.lastname: Xing
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Maheswari
authors.initials: M
authors.lastname: Senthil
authors.forename: Yasir
authors.initials: Y
authors.lastname: Akmal
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Kowolik
authors.forename: Julia
authors.initials: J
authors.lastname: Kang
authors.forename: David M
authors.initials: DM
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Zhixiu
authors.initials: Z
authors.lastname: Lin
authors.forename: Christopher H K
authors.initials: CH
authors.lastname: Cheng
authors.forename: M L Richard
authors.initials: ML
authors.lastname: Yip
authors.forename: John H
authors.initials: JH
authors.lastname: Yim
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D044950:Flavanones; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D014157:Transcription Factors; C006680:baicalein