A Perspective on Dietary Phytochemicals and Cancer Chemoprevention: Oxidative Stress, Nrf2, and Epigenomics

Abstract

Oxidative stress is caused by an imbalance of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the antioxidative stress defense systems in cells. ROS/RNS or carcinogen metabolites can attack intracellular proteins, lipids, and nucleic acids, which can result in genetic mutations, carcinogenesis, and other diseases. Nrf2 plays a critical role in the regulation of many antioxidative stress/antioxidant and detoxification enzyme genes, such as glutathione Stransferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1), UDP-glucuronyl transferases (UGTs), and heme oxygenase-1 (HO-1), directly via the antioxidant response element (ARE). Recently, many studies have shown that dietary phytochemicals possess cancer chemopreventive potential through the induction of Nrf2-mediated antioxidant/detoxification enzymes and antiinflammatory signaling pathways to protect organisms against cellular damage caused by oxidative stress. In addition, carcinogenesis can be caused by epigenetic alterations such as DNA methylation and histone modifications in tumor-suppressor genes and oncogenes. Interestingly, recent studies have shown that several naturally occurring dietary phytochemicals can epigenetically modify the chromatin, including reactivating Nrf2 via demethylation of CpG NIH Public Access islands and the inhibition of histone deacetylases (HDACs) and/or histone acetyltransferases (HATs). The advancement and development of dietary phytochemicals in cancer chemoprevention research requires the integration of the known, and as-yet-unknown, compounds with the Nrf2-mediated antioxidant, detoxification, and anti-inflammatory systems and their in vitro and in vivo epigenetic mechanisms; human clinical efficacy studies must also be performed.

Requirement and Epigenetics Reprogramming of Nrf2 in Suppression of Tumor Promoter TPA-Induced Mouse Skin Cell Transformation by Sulforaphane

“…The transcriptional activation of antioxidant and detoxification genes is increased by Nrf2 through its interaction with AREs (34), and accumulating evidence indicates that dietary phytochemicals with chemopreventive potential could enhance the activities of antioxidant and detoxification enzymes via the Nrf2 pathway (35). This study shows that SFN increased HO-1, NQO1, and UGT1A1 mRNA and protein levels as well as the nuclear translocation and expression of total endogenous Nrf2 protein in JB6 Pþ cells (Fig.…”

Reserpine Inhibit the JB6 P+ Cell Transformation Through Epigenetic Reactivation of Nrf2-Mediated Anti-oxidative Stress Pathway

“…Once the interaction of Keap1 and Nrf2 is disrupted and cytoplasmic and nuclear Nrf2 accumulates, Nrf2 binds to the ARE in the promoter region of some phase II enzyme genes and triggers the expression of Nrf2 downstream enzymes (59)(60)(61). Therefore, many dietary phytochemicals with chemopreventive potential have been reported to enhance the activities of phase II enzymes through the Nrf2-ARE pathway (20). Interestingly, the results of this study showed reserpineinduced ARE-luciferase activity in HepG2-C8 cells (Fig.…”

“…In addition, we recently demonstrated that Nrf2 is downregulated during 12-Otetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of mouse skin epidermis JB6 P+ cells (18). The deregulation of the antioxidant defense system has received increased attention because this complication promotes susceptibility and neoplastic progression (18)(19)(20)(21).…”

Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance

“…Interestingly, NRF2 activity is restored by phytochemicals that reduce methylation of CG islands (297). With regard to oxidative stress, AD patients display high homocysteine and low vitamin B 12 and folate levels in blood, suggesting a dysregulation of the S-adenosyl methionine cycle that is required for DNA methylation (275).…”