PUBLICATION
1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic {alpha},{beta}-unsaturated aldehyde acrolein
- Authors
- Kelleher, M.O., McMahon, M., Eggleston, I.M., Dixon, M.J., Taguchi, K., Yamamoto, M., and Hayes, J.D.
- ID
- ZDB-PUB-090731-5
- Date
- 2009
- Source
- Carcinogenesis 30(10): 1754-1762 (Journal)
- Registered Authors
- Yamamoto, Masayuki
- Keywords
- cancer chemoprevention, epithionitriles, glucosinolates, NAD(P)H:quinone oxidoreductase 1, Nrf2, Keap1
- MeSH Terms
-
- Acrolein/antagonists & inhibitors*
- Animals
- Antioxidants/pharmacology
- Cell Survival/drug effects
- Epithelial Cells/cytology
- Epithelial Cells/drug effects
- Genes, Reporter/drug effects
- Glucosinolates/metabolism
- Glutathione/metabolism
- Liver/cytology
- Liver/physiology
- Luciferases/genetics
- Mice
- Nitriles/metabolism
- Nitriles/pharmacology*
- Plant Extracts/pharmacology*
- Propane/analogs & derivatives*
- Propane/pharmacology
- RNA, Messenger/drug effects
- RNA, Messenger/genetics
- Rats
- Sulfhydryl Compounds/pharmacology*
- Transcription, Genetic/drug effects*
- PubMed
- 19633057 Full text @ Carcinogenesis
Citation
Kelleher, M.O., McMahon, M., Eggleston, I.M., Dixon, M.J., Taguchi, K., Yamamoto, M., and Hayes, J.D. (2009) 1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic {alpha},{beta}-unsaturated aldehyde acrolein. Carcinogenesis. 30(10):1754-1762.
Abstract
Epithionitriles represent a previously unrecognised class of cancer chemopreventive phytochemical generated from alkenyl glucosinolates in cruciferous vegetables. In rat liver RL-34 epithelial cells, 1-cyano-2,3-epithiopropane (CETP), 1-cyano-3,4-epithiobutane (CETB) and 1-cyano-4,5-epithiopentane (CETPent) were shown to induce cytoprotective enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase A3, and the glutamate-cysteine ligase modifier subunit; CETP was more potent in this regard than were either CETB or CETPent, with 50 muM CETP eliciting a remarkable approximately 10-fold induction of NQO1. Furthermore, 50 muM CETP stimulated a 2.0-fold overproduction of glutathione in RL-34 cells. Transfection experiments demonstrated that epithionitriles induced gene expression through an antioxidant response element (ARE), and that transactivation of a Nqo1-luciferase reporter plasmid was dependent on NF-E2 p45-related factor 2 (Nrf2), a cap'n'collar basic-region leucine zipper transcription factor. Evidence is presented that CETP affected Nrf2-mediated induction of ARE-driven transcription by inhibiting Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase substrate adaptor that negatively regulates Nrf2. We found that Nqo1 was expressed constitutively at high levels in Keap1(-/-) mouse embryonic fibroblasts (MEFs) and it was not further induced by CETP. However, knock-in of mouse Keap1 or zebrafish Keap1a into Keap1(-/-) MEFs repressed Nqo1-luciferase reporter gene activity, but repression by the murine or zebrafish proteins was antagonised by CETP. Pre-treatment of Nrf2(+/+) MEFs, but not Nrf2(-/-) MEFs, with 15 muM CETP for 24 h conferred 2.4-fold resistance against subsequent exposure to the alpha,beta-unsaturated aldehyde acrolein, indicating the phytochemical exerts chemopreventive properties against genotoxic xenobiotics.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping