Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole

Melinda S. Yates, Mi Kyoung Kwak, Patricia A. Egner, John D. Groopman, Sridevi Bodreddigari, Thomas R. Sutter, Karen J. Baumgartner, B. D. Roebuck, Karen T. Liby, Mark M. Yore, Tadashi Honda, Gordon W. Gribble, Michael B. Sporn, Thomas W. Kensler

Research output: Contribution to journalArticle

Abstract

Synthetic triterpenoid analogues of oleanolic acid are potent inducers of the phase 2 response as well as inhibitors of inflammation. We show that the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), is a highly potent chemopreventive agent that inhibits aflatoxin-induced tumorigenesis in rat liver. The chemopreventive potency of CDDO-Im was evaluated by measuring inhibition of formation of putative preneoplastic lesions (glutathione S-transferase P positive foci) in the liver of rats exposed to aflatoxin B1. CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 μmol/ kg body weight and a >99% reduction at 100 μmol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by ∼40% to 90% over the range of 1 to 100 μmol/kg body weight. Additionally, changes in mRNA levels of genes involved in aflatoxin metabolism were measured in rat liver following a single dose of CDDO-Im. GSTA2, GSTA5, AFAR, and EPHX1 transcripts are elevated 6 hours following a 1 μmol/kg body weight dose of CDDO-Im. Microarray analysis using wild-type and Nrf2 knockout mice confirms that many phase 2 and antioxidant genes are induced in an Nrf2-dependent manner in mouse liver following treatment with CDDO-Im. Thus, low-micromole doses of CDDO-Im induce cytoprotective genes, inhibit DNA adduct formation, and dramatically block hepatic tumorigenesis. As a point of reference, oltipraz, an established modulator of aflatoxin metabolism in humans, is 100-fold weaker than CDDO-Im in this rat antitumorigenesis model. The unparalleled potency of CDDO-Im in vivo highlights the chemopreventive promise of targeting Nrf2 pathways with triterpenoids.

Original languageEnglish (US)
Pages (from-to)2488-2494
Number of pages7
JournalCancer Research
Volume66
Issue number4
DOIs
StatePublished - Feb 15 2006

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yates, M. S., Kwak, M. K., Egner, P. A., Groopman, J. D., Bodreddigari, S., Sutter, T. R., Baumgartner, K. J., Roebuck, B. D., Liby, K. T., Yore, M. M., Honda, T., Gribble, G. W., Sporn, M. B., & Kensler, T. W. (2006). Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole. Cancer Research, 66(4), 2488-2494. https://doi.org/10.1158/0008-5472.CAN-05-3823