Abstract 861: Nrf2-mediated induction of heme oxygenase-1 expression by cyclopentenone prostaglandin analogues in human breast epithelial cells: Structure-activity relationships

Abstract

Abstract 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor γ, has been known to induce heme oxygenase-1 (HO-1) in certain cell lines. The mechanism by which 15d-PGJ2 upregulates HO-1 expression is considered to involve covalent modifications of critical cysteine residues of Keap1, a cytoplasmic repressor of Nrf2. This facilitates dissociation of Nrf2 from Keap1 for nuclear translocation and binding to the antioxidant response element. In the present work, we synthesized a series of 15d-PGJ2 analogues: i) Halogenated 15d-PGJ2 derivatives by introducing an electron withdrawing group, i.e., halogen into the electrophilic carbon; ii) Olefin modified 15d-PGJ2 analogues by saturating an electrophilic α,β-unsaturated carbonyl moiety in the cyclopentenone ring; iii) Combined halogenated and olefin modified 15d-PGJ2 analogues with more potent electrophilic nature to form stable Keap1 adducts. Twelve 15d-PGJ2 analogues were synthesized that retain the essential structural features of 15d-PGJ2 with different capabilities to induce Nrf2 activation. When treated to the human breast epithelial cell line (MCF10A), halogenated 15d-PGJ2 analogues were found to have high potency and efficacy for inducing HO-1 expression as well as Nrf2 activation (-Cl > -Br > -F = -I). 14,15-Dihydro-PGJ2 also retains capability to induce HO-1 expression and Nrf2 activation. However, abilities of both 9,10-dihydro-15d-PGJ2 and 12,13-14,15-tetrahydro-PGJ2 to induce HO-1 expression and Nrf2 activation were abolished due to lack of the electrophilic α,β-unsaturated carbonyl moiety. Chlorinated 14,15-dihydro-PGJ2 has the highest potency and efficacy for HO-1 induction via Nrf2 activation. We further showed that biotinylated 15d-PGJ2 directly bound to Keap1, which was confirmed by avidin pull-down. Biotinylated chloro 14,15-dihydro-PGJ2 interacted with Keap1 to a greater extent than did 15d-PGJ2. In contrast to 15d-PGJ2, 9,10-dihydro-15d-PGJ2 failed to modify Keap1. Taken together, these results suggest that 15d-PGJ2 containing an electrophilic cyclopentenone moiety can directly modify Keap1, presumably at its critical cysteine residue. As halogenated 15d-PGJ2 analogues and 14,15-dihydro-PGJ2 can stably interact with Keap1, they can be utilized as lead compounds for the development of anti-inflammatory and chemopreventive agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2011-861