Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system

Karin Linnewiel, Hansgeorg Ernst, Catherine Caris-Veyrat, Anat Ben-Dor, Arie Kampf, Hagar Salman, Michael Danilenko, Joseph Levy, Yoav Sharoni

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

Induction of phase II detoxifying enzymes is a major cellular strategy for reducing the risk of cancer. We previously reported that carotenoids activate the electrophile/antioxidant response element (EpRE/ARE) transcription system and induced the expression of phase II enzymes. Various electrophilic phytonutrients have been shown to induce the EpRE/ARE system by disrupting the inhibitory activity of Keap1 on Nrf2, the major EpRE/ARE activating transcription factor. However, hydrophobic carotenoids such as lycopene lack any electrophilic group and, thus, are unlikely to directly activate Nrf2 and the EpRE/ARE system. Here we demonstrate that carotenoid oxidation products are the active mediators in the stimulation of the EpRE/ARE system by carotenoids. Two lines of evidence support this conclusion. (A) The oxidized derivatives, extracted by ethanol from partially oxidized lycopene, transactivated EpRE/ARE with a potency similar to that of the unextracted lycopene mixture, whereas the intact carotenoid showed a nonsignificant effect. (B) Using a series of characterized mono- and diapocarotenoids that potentially can be derived from in vivo metabolism of carotenoids we defined the following structure-activity rules for activation of EpRE/ARE: (I) aldehydes and not acids are the active molecules; (II) the activity depends on the relative position of the methyl group to the terminal aldehyde which determines the reactivity of the conjugated double bond; (III) the optimal length of a dialdehyde derivative is 12 carbons in the main chain of the molecule. The apocarotenals inhibited breast and prostate cancer cell growth with a similar order of potency to the activation of EpRE/ARE. These results may provide a mechanistic explanation for the cancer preventive activity of carotenoids.

Original languageEnglish
Pages (from-to)659-667
Number of pages9
JournalFree Radical Biology and Medicine
Volume47
Issue number5
DOIs
StatePublished - 1 Sep 2009

Keywords

  • Apocarotenals
  • Breast cancer
  • Carotenoids
  • Diapocarotene-dials
  • EpRE/ARE
  • LNCaP
  • Lycopene
  • MCF-7
  • Nrf2
  • Prostate cancer
  • T47D

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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