Journal Article

1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic α,β-unsaturated aldehyde acrolein

Michael O. Kelleher, Michael McMahon, Ian M. Eggleston, Mark J. Dixon, Keiko Taguchi, Masayuki Yamamoto and John D. Hayes

in Carcinogenesis

Volume 30, issue 10, pages 1754-1762
Published in print October 2009 | ISSN: 0143-3334
Published online July 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp182
1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic α,β-unsaturated aldehyde acrolein

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Epithionitriles represent a previously unrecognized 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 (GSH) 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 μM CETP eliciting a remarkable ∼10-fold induction of NQO1. Furthermore, 50 μM CETP stimulated a 2.0-fold overproduction of GSH in RL-34 cells. Transfection experiments demonstrated that epithionitriles induced gene expression through an antioxidant response element (ARE) and that transactivation of an 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 antagonized by CETP. Pre-treatment of Nrf2+/+ MEFs, but not Nrf2−/− MEFs, with 15 μM CETP for 24 h conferred 2.4-fold resistance against subsequent exposure to the α,β-unsaturated aldehyde acrolein, indicating that the phytochemical exerts chemopreventive properties against genotoxic xenobiotics.

Journal Article.  7710 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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