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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.

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-... Full description

Journal Title: Cancer research February 15, 2006, Vol.66(4), pp.2488-2494
Main Author: Yates, Melinda S
Other Authors: Kwak, Mi-Kyoung , Egner, Patricia A , Groopman, John D , Bodreddigari, Sridevi , Sutter, Thomas R , Baumgartner, Karen J , Roebuck, B D , Liby, Karen T , Yore, Mark M , Honda, Tadashi , Gribble, Gordon W , Sporn, Michael B , Kensler, Thomas W
Format: Electronic Article Electronic Article
Language: English
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ID: ISSN: 0008-5472
Link: http://search.proquest.com/docview/67670478/?pq-origsite=primo
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title: 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.
format: Article
creator:
  • Yates, Melinda S
  • Kwak, Mi-Kyoung
  • Egner, Patricia A
  • Groopman, John D
  • Bodreddigari, Sridevi
  • Sutter, Thomas R
  • Baumgartner, Karen J
  • Roebuck, B D
  • Liby, Karen T
  • Yore, Mark M
  • Honda, Tadashi
  • Gribble, Gordon W
  • Sporn, Michael B
  • Kensler, Thomas W
subjects:
  • Aflatoxin B1–Metabolism
  • Animals–Pharmacokinetics
  • Anticarcinogenic Agents–Toxicity
  • DNA Adducts–Pharmacology
  • Gene Expression Regulation, Neoplastic–Metabolism
  • Imidazoles–Drug Effects
  • Inactivation, Metabolic–Pharmacology
  • Liver–Metabolism
  • Liver Neoplasms, Experimental–Chemically Induced
  • Male–Metabolism
  • Nf-E2-Related Factor 2–Prevention & Control
  • Oleanolic Acid–Biosynthesis
  • Rats–Metabolism
  • Rats, Inbred F344–Analogs & Derivatives
  • Rats, Inbred F344–Pharmacology
  • 1-(2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oyl) Imidazole
  • Anticarcinogenic Agents
  • DNA Adducts
  • Imidazoles
  • Nf-E2-Related Factor 2
  • Aflatoxin B1-DNA Adduct
  • Oleanolic Acid
  • Aflatoxin B1
ispartof: Cancer research, February 15, 2006, Vol.66(4), pp.2488-2494
description: 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 B sub(1). CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 mu mol/kg body weight and a >99% reduction at 100 mu mol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by similar to 40% to 90% over the range of 1 to 100 mu mol/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 mu mol/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. (Cancer Res 2006; 66(4): 2488-94)
language: eng
source:
identifier: ISSN: 0008-5472
fulltext: fulltext
issn:
  • 00085472
  • 0008-5472
url: Link


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titlePotent 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.
creatorYates, Melinda S ; Kwak, Mi-Kyoung ; Egner, Patricia A ; Groopman, John D ; Bodreddigari, Sridevi ; Sutter, Thomas R ; Baumgartner, Karen J ; Roebuck, B D ; Liby, Karen T ; Yore, Mark M ; Honda, Tadashi ; Gribble, Gordon W ; Sporn, Michael B ; Kensler, Thomas W
contributorYates, Melinda S (correspondence author) ; Yates, Melinda S (record owner)
ispartofCancer research, February 15, 2006, Vol.66(4), pp.2488-2494
identifierISSN: 0008-5472
subjectAflatoxin B1–Metabolism ; Animals–Pharmacokinetics ; Anticarcinogenic Agents–Toxicity ; DNA Adducts–Pharmacology ; Gene Expression Regulation, Neoplastic–Metabolism ; Imidazoles–Drug Effects ; Inactivation, Metabolic–Pharmacology ; Liver–Metabolism ; Liver Neoplasms, Experimental–Chemically Induced ; Male–Metabolism ; Nf-E2-Related Factor 2–Prevention & Control ; Oleanolic Acid–Biosynthesis ; Rats–Metabolism ; Rats, Inbred F344–Analogs & Derivatives ; Rats, Inbred F344–Pharmacology ; 1-(2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oyl) Imidazole ; Anticarcinogenic Agents ; DNA Adducts ; Imidazoles ; Nf-E2-Related Factor 2 ; Aflatoxin B1-DNA Adduct ; Oleanolic Acid ; Aflatoxin B1
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descriptionSynthetic 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 B sub(1). CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 mu mol/kg body weight and a >99% reduction at 100 mu mol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by similar to 40% to 90% over the range of 1 to 100 mu mol/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 mu mol/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. (Cancer Res 2006; 66(4): 2488-94)
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titlePotent 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.
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titlePotent 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.
authorYates, Melinda S ; Kwak, Mi-Kyoung ; Egner, Patricia A ; Groopman, John D ; Bodreddigari, Sridevi ; Sutter, Thomas R ; Baumgartner, Karen J ; Roebuck, B D ; Liby, Karen T ; Yore, Mark M ; Honda, Tadashi ; Gribble, Gordon W ; Sporn, Michael B ; Kensler, Thomas W
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5Imidazoles–Drug Effects
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atitlePotent 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.
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