Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Abstract

Strong experimental evidence suggests the involvement of photo-oxidative stress mediated by reactive oxygen species as a crucial mechanism of solar damage relevant to human skin photoaging and photocarcinogenesis. Based on the established role of antioxidant response element (ARE)-mediated gene expression in cancer chemoprevention, we tested the hypothesis that small molecule Nrf2-activators may serve a photo-chemopreventive role by targeting skin cell photo-oxidative stress. A luciferase-based reporter gene assay was used as a primary screen for the identification of novel agents that modulate the Nrf2-Keap1 signaling pathway. A series of cinnamoyl-based electrophilic Michael acceptors including cinnamic aldehyde and methyl-1-cinnamoyl-5-oxo-2-pyrrolidine-carboxylate was identified as potent Nrf2-activators. Hit confirmation was performed in a secondary screen, based on immunodetection of Nrf2 protein upregulation in human Hs27 skin fibroblasts, HaCaT keratinocytes, and primary skin keratinocytes. Bioefficacy profiling of positive test compounds in skin cells demonstrated compound-induced upregulation of hemeoxygenase I and NAD(P)H-quinone oxidoreductase, two Nrf2 target genes involved in the cellular antioxidant response. Pretreatment with cinnamoylbased Nrf2-activators suppressed intracellular oxidative stress and protected against photooxidative induction of apoptosis in skin cells exposed to high doses of singlet oxygen. Our pilot studies suggest feasibility of developing cinnamoyl-based Nrf2-activators as novel photochemopreventive agents targeting skin cell photo-oxidative stress.

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…8C-50) (47,152,169,380). CA contains a Michael acceptor pharmacophore that displays attenuated reactivity towards thiol adduction due to aromatic conjugation with the adjacent benzene ring.…”

“…CA contains a Michael acceptor pharmacophore that displays attenuated reactivity towards thiol adduction due to aromatic conjugation with the adjacent benzene ring. CA spontaneously forms covalent adducts with model thiols and activates Nrf2-regulated antioxidant response element (ARE)-mediated gene expression (380). Nonaldehyde cinnamoyl derivatives with further attenuated Michael acceptor reactivity have been designed serving as noncytotoxic experimental Nrf2 activators for skin cell protection against photooxidative stress (380).…”

Conformational behaviour of biologically active ferulic acid derivatives

“…Minimum energy conformations displaying (C 4 -C 5 -O 8 -C 17 ) and (C 5 -C 6 -O 7 -H 18 ) dihedrals equal to 120°and 180°, respectively, were also found. These non-planar geometries (e.g.…”

“…Hydroxycinnamic acids and hydroxycinnamates have received particular attention in the past 10 years, since their potential health benefits have been discovered, namely in the prevention of several human diseases related with the oxidative stress [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. They are an integral part of a diet rich in fruit, vegetables and beverages and may scavenge free-radical oxygen species both in vitro and in vivo [18][19][20].…”

The dark side of the light: mechanisms of photocarcinogenesis

“…6 Indirect DNA damage Unlike UVB, the less energetic UVA radiation is very weakly absorbed by DNA; rather, UVA may be absorbed by other endogenous chromophores such as cytochromes, flavin, heme, NAD(P)H, porphyrins, and collagen crosslinks. 18,19 Its genotoxic and cytotoxic actions are the result of photodynamic effects that are strongly oxygen-dependent (Figure 2). 6,[12][13][14]18 Once UVR is absorbed, mutagenic oxidative reactions between the excited chromophores and cellular DNA may be triggered via two main mechanisms 6,[12][13][14]18 : In type I photosensitized reactions the energy is directly transferred to DNA, whereas in type II photosensitized reactions the energy is transferred to molecular oxygen, with DNA damage occurring via ensuing reactive oxygen species (ROS).…”