The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling

Karen Liby, Thomas Hock, Mark M. Yore, Nanjoo Suh, Andrew E. Place, Renee Risingsong, Charlotte R. Williams, Darlene B. Royce, Tadashi Honda, Yukiko Honda, Gordon W. Gribble, Nathalie Hill-Kapturczak, Anupam Agarwal, Michael B. Sporn

Research output: Contribution to journalArticlepeer-review

216 Scopus citations

Abstract

The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its derivative 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im) are multifunctional molecules with potent antiproliferative, differentiating, and anti-inflammatory activities. At nanomolar concentrations, these agents rapidly increase the expression of the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. Transfection studies using a series of reporter constructs show that activation of the human HO-1 promoter by the triterpenoids requires an antioxidant response element (ARE), a cyclic AMP response element, and an E Box sequence. Inactivation of one of these response elements alone partially reduces HO-1 induction, but mutations in all three sequences entirely eliminate promoter activity in response to the triterpenoids. Treatment with CDDO-Im also elevates protein levels of Nrf2, a transcription factor previously shown to bind ARE sequences, and increases expression of a number of antioxidant and detoxification genes regulated by Nrf2. The triterpenoids also reduce the formation of reactive oxygen species in cells challenged with tert-butyl hydroperoxide, but this cytoprotective activity is absent in Nrf2 deficient cells. These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and our results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids.

Original languageEnglish (US)
Pages (from-to)4789-4798
Number of pages10
JournalCancer Research
Volume65
Issue number11
DOIs
StatePublished - Jun 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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