Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold.

Abstract

In experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects against AFB1-induced toxicity and preneoplastic lesion formation (GST-P-positive foci). This study assessed and mechanistically characterized the chemoprotective efficacy of CDDO-Im against AFB1-induced hepatocellular carcinoma (HCC). A lifetime cancer bioassay was undertaken in F344 rats dosed with AFB1 (200 μg/kg rat/day) for four weeks and receiving either vehicle or CDDO-Im (three times weekly), one week before and throughout the exposure period. Weekly, 24-hour urine samples were collected for analysis of AFB1 metabolites. In a subset of rats, livers were analyzed for GST-P foci. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined. CDDO-Im completely protected (0/20) against AFB1-induced liver cancer compared with a 96% incidence (22/23) observed in the AFB1 group. With CDDO-Im treatment, integrated level of urinary AFB1-N(7)-guanine was significantly reduced (66%) and aflatoxin-N-acetylcysteine, a detoxication product, was consistently elevated (300%) after the first AFB1 dose. In AFB1-treated rats, the hepatic burden of GST-P-positive foci increased substantially (0%-13.8%) over the four weeks, but was largely absent with CDDO-Im intervention. The toxicogenomic RNA expression signature characteristic of AFB1 was absent in the AFB1 + CDDO-Im-treated rats. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development.

• Authors: Natalie M Johnson, Patricia A Egner, Victoria K Baxter, Michael B Sporn, Ryan S Wible, Thomas R Sutter, John D Groopman, Thomas W Kensler, Bill D Roebuck
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 7 Issue 7 Pg. 658-65 (Jul 2014) ISSN: 1940-6215 [Electronic] United States
• PMID: 24662598 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Biomarkers, Tumor
• DNA Adducts
• Imidazoles
• Poisons
• aflatoxin B1-DNA adduct
• Oleanolic Acid
• Aflatoxin B1
• Glutathione S-Transferase pi
• Gstp1 protein, rat

Topics

• Aflatoxin B1 (metabolism, toxicity)
• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Hepatocellular (chemically induced, metabolism, prevention & control)
• DNA Adducts (metabolism)
• DNA Damage (drug effects)
• Dose-Response Relationship, Drug
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Glutathione S-Transferase pi (metabolism)
• Imidazoles (therapeutic use)
• Liver Neoplasms, Experimental (chemically induced, metabolism, prevention & control)
• Male
• Oleanolic Acid (analogs & derivatives, therapeutic use)
• Oligonucleotide Array Sequence Analysis
• Poisons (toxicity)
• Precancerous Conditions (chemically induced, metabolism, prevention & control)
• Rats
• Rats, Inbred F344