title: TPA-induced up-regulation of activator protein-1 can be inhibited or enhanced by analogs of the natural product curcumin.
abstract: The activator protein-1 (AP-1) family of transcription factors, including the most common member c-Jun-c-Fos, participates in regulation of expression of numerous genes involved in proliferation, apoptosis, and tumorigenesis in response to a wide array of stimuli including pro-inflammatory cytokines, growth factors, stress, and tumor promoters. A number of plant polyphenols including curcumin, a yellow compound in the spice turmeric, have been shown to inhibit the activation of AP-1. Curcumin is a polyphenolic dienone that is potentially reactive as a Michael acceptor and also is a strong anti-oxidant. Multiple activities reported for curcumin, including inhibition of the stress-induced activation of AP-1, have been suggested to involve the anti-oxidant properties of curcumin. In the present study, a library of analogs of curcumin was screened for activity against the TPA-induced activation of AP-1 using the Panomics AP-1 Reporter 293 stable cell line which is designed for screening potential inhibitors. Numerous analogs were identified that were more active than curcumin, including analogs that were not anti-oxidants and analogs that were not Michael acceptors. Clearly, anti-oxidant activity or reactivity as a Michael acceptor is not an essential feature of active compounds. In addition, a number of analogs were identified that enhanced the TPA-induced activation of AP-1. The results from screening were confirmed using BV-2 microglial cells where curcumin and analogs were shown to inhibit LPS-induced COX-2 expression; analogs identified as more potent than curcumin in the screening assay were also more potent than curcumin in preventing COX-2 expression.
authors.affiliation: Department of Chemistry, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Waylon M
authors.initials: WM
authors.lastname: Weber
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Hunsaker
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gonzales
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Heynekamp
authors.forename: Robert A
authors.initials: RA
authors.lastname: Orlando
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Deck
authors.forename: David L
authors.initials: DL
authors.lastname: Vander Jagt
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; D003474:Curcumin; D013755:Tetradecanoylphorbol Acetate