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

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 11; pp. 4789 - 4798
• Main Authors: LIBY, Karen, HOCK, Thomas, GRIBBLE, Gordon W, HILL-KAPTURCZAK, Nathalie, AGARWAL, Anupam, SPORN, Michael B, YORE, Mark M, SUH, Nanjoo, PLACE, Andrew E, RISINGSONG, Renee, WILLIAMS, Charlotte R, ROYCE, Darlene B, HONDA, Tadashi, HONDA, Yukiko
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2005
• Subjects: Animals; Antineoplastic agents; Antioxidants - physiology; Biological and medical sciences; Cell Line, Tumor; Cyclic AMP - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; DNA-Binding Proteins - physiology; Enzyme Induction - drug effects; Gene Expression Regulation, Leukemic; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - biosynthesis; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Humans; Imidazoles - pharmacology; Medical sciences; Membrane Proteins; Mice; NF-E2-Related Factor 2; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Oxidative Stress; Pharmacology. Drug treatments; Phosphorylation; Promoter Regions, Genetic; Response Elements - drug effects; Response Elements - physiology; Signal Transduction - drug effects; Trans-Activators - physiology; Transfection; Tumors; U937 Cells; Terpenoid; Signal transduction; Synthetic product; Signaling pathway; Enzyme; Triterpene; Heme oxygenase (decyclizing); Oxidoreductases
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-4539

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.