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

• Published in: Free radical biology & medicine Vol. 47; no. 5; pp. 659 - 667
• Main Authors: Linnewiel, Karin, Ernst, Hansgeorg, Caris-Veyrat, Catherine, Ben-Dor, Anat, Kampf, Arie, Salman, Hagar, Danilenko, Michael, Levy, Joseph, Sharoni, Yoav
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2009
• Subjects: Aldehydes - chemistry; Aldehydes - pharmacology; Antioxidants - metabolism; Apocarotenals; Breast cancer; Carcinoma - genetics; Carcinoma - metabolism; Carotenoids; Carotenoids - chemistry; Carotenoids - metabolism; Carotenoids - pharmacology; Cell Proliferation - drug effects; Diapocarotene-dials; Drug Screening Assays, Antitumor; EpRE/ARE; Gene Expression Regulation, Neoplastic - drug effects; Humans; LNCaP; Lycopene; Male; MCF-7; Models, Biological; Nrf2; Oxidation-Reduction; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Response Elements - drug effects; Response Elements - physiology; Structure-Activity Relationship; T47D; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Transcriptional Activation - drug effects; Tumor Cells, Cultured; LNCaP; DMSO; 10′-acid; MCF-7; 8,15-acid; RXR; BHT; DCC-FCS; Apocarotenals; DHT; THF; Carotenoids; PPAR; Nrf2; EpRE/ARE; 10,10′10; 10′-al; NQO1; tBHQ; Diapocarotene-dials; Breast cancer; T47D; Lycopene; CMO2; CMO1; Prostate cancer
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2009.06.008

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.