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Cited by 283Heme Oxygenase-1 and Carbon MonoxideGenomics, phytochemicals, and oxidative stressNatural product bioactivities and synthesis

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

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Liby, Karen, Hock, Thomas, Yore, Mark M., Suh, Nanjoo, Place, Andrew E., Risingsong, Renee, Williams, Charlotte R., Royce, Darlene B. +6 more·2005·Cancer Research
DOI 10.1158/0008-5472.can-04-4539
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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.

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  • CDDO is a synthesized triterpenoid that potently activates Nrf2, promotes its nuclear translocation, and induces expression of downstream antioxidant proteins such as NQO1 and HO-1.

    “CDDO is a synthesized triterpenoid that potently activates Nuclear factor erythroid 2–related factor 2 (Nrf2), promotes its nuclear translocation (Kurosaki et al., 2022), and induces the expression of downstream antioxidant proteins such as NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase 1 (HO-1) (Liby et al., 2005).”

    From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Liby et al., 2005

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Cited by

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Authors
Liby, K., Hock, T., Yore, M. M., Suh, N., Place, A. E., Risingsong, R., Williams, C. R., Royce, D. B., Honda, T., Honda, Y., Gribble, G. W., Hill-Kapturczak, N., Agarwal, A., & Sporn, M. B.
Affiliations
  • 1Dartmouth Medical School and
  • University of Alabama at Birmingham (US)
  • Dartmouth College (US)
  • 3University of Alabama at Birmingham, Birmingham, Alabama
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2005-06-01
Volume
65
Issue
11
Pages
4789-4798
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-04-4539
OpenAlex
W2164552211
Cited by
283
References
2
Citations by year
2026: 9 · 2025: 11 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 14 · 2019: 8 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 23 · 2014: 22 · 2013: 21 · 2012: 26
FWCI
4.90
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Dartmouth College
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL068157)
  • National Cancer Institute (K22CA099990, K22 CA99990-02, R01CA078814)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK059600)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
Keywords
CDDO, synthetic triterpenoids, heme oxygenase-1, Nrf2, antioxidant response element, promoter regulation, reactive oxygen species, chemoprevention, cytoprotection
MeSH terms
Cyclic AMP, Animals, Antioxidants, DNA-Binding Proteins, Enzyme Induction, Heme Oxygenase (Decyclizing), Humans, Imidazoles, Membrane Proteins, Oleanolic Acid, Phosphorylation, Promoter Regions, Genetic, Transfection, Signal Transduction, Trans-Activators, Gene Expression Regulation, Leukemic, Cyclic AMP Response Element-Binding Protein, Oxidative Stress, Response Elements, U937 Cells, Cell Line, Tumor, NF-E2-Related Factor 2, Mice, Heme Oxygenase-1

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