TPA-induced up-regulation of activator protein-1 can be inhibited or enhanced by analogs of the natural product curcumin

Biochem Pharmacol. 2006 Oct 16;72(8):928-40. doi: 10.1016/j.bcp.2006.07.007. Epub 2006 Aug 28.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Cell Line
  • Curcumin / analogs & derivatives
  • Curcumin / pharmacology*
  • Cyclooxygenase 2 / metabolism
  • Humans
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Transcription Factor AP-1 / agonists
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / metabolism*
  • Up-Regulation


  • Antioxidants
  • Transcription Factor AP-1
  • Cyclooxygenase 2
  • Curcumin
  • Tetradecanoylphorbol Acetate