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

Kelleher, M.O., McMahon, M., Eggleston, I.M., Dixon, M.J., Taguchi, K., Yamamoto, M., and Hayes, J.D.
Carcinogenesis   30(10): 1754-1762 (Journal)
Registered Authors
Yamamoto, Masayuki
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*
19633057 Full text @ Carcinogenesis
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
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes