Cancer Chemoprevention by Traditional Chinese Herbal Medicine and Dietary Phytochemicals: Targeting Nrf2-Mediated Oxidative Stress/Anti-Inflammatory Responses, Epigenetics, and Cancer Stem Cells

Abstract

Excessive oxidative stress induced by reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive metabolites of carcinogens alters cellular homeostasis, leading to genetic/epigenetic changes, genomic instability, neoplastic transformation, and cancer initiation/progression. As a protective mechanism against oxidative stress, antioxidant/detoxifying enzymes reduce these reactive species and protect normal cells from endo-/exogenous oxidative damage. The transcription factor nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2), a master regulator of the antioxidative stress response, plays a critical role in the expression of many cytoprotective enzymes, including NAD(P)H:quinine oxidoreductase (NQO1), heme oxygenase-1 (HO-1), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). Recent studies demonstrated that many dietary phytochemicals derived from various vegetables, fruits, spices, and herbal medicines induce Nrf2-mediated antioxidant/detoxifying enzymes, restore aberrant epigenetic alterations, and eliminate cancer stem cells (CSCs). The Nrf2-mediated antioxidant response prevents many age-related diseases, including cancer. Owing to their fundamental contribution to carcinogenesis, epigenetic modifications and CSCs are novel targets of dietary phytochemicals and traditional Chinese herbal medicine (TCHM). In this review, we summarize cancer chemoprevention by dietary phytochemicals, including TCHM, which have great potential as a safer and more effective strategy for preventing cancer.

Dietary Glucosinolates Sulforaphane, Phenethyl Isothiocyanate, Indole-3-Carbinol/3,3′-Diindolylmethane: Antioxidative Stress/Inflammation, Nrf2, Epigenetics/Epigenomics and In Vivo Cancer Chemopreventive Efficacy

“…Consequently, the oxidative stress produced by high levels of ROS/RNS during normal cell metabolism leads to potential damage, causing oxidative damage to large biomolecules, such as lipids, proteins, and DNA, which may eventually lead to mutations and ultimately, cancer development [25]. Similarly, oxidative stress also has a significant association with many other chronic diseases, such as neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), cardiovascular disease, diabetes, and inflammatory diseases [26-28]. In this context, the major chemoprevention mechanisms mediated by dietary glucosinolate derivatives include modulation of phase I drug metabolic enzymes (e.g., cytochrome P450 family, CYP), which prevent procarcinogenic molecule formation and the induction of phase II/detoxifying enzymes (e.g., GST; UDPglucuronosyl transferases, and UGT), which catalyze conjugation reactions to inactivate or detoxify exogenous (e.g., carcinogens and other xenobiotics) and endogenous compounds (e.g., sex steroid hormones) related to cancer development [29-31].…”

“…Recently, a large amount of evidence has demonstrated that epigenetic alterations, such as DNA methylation, histone modifications and non-coding miRNAs, consistently contribute to carcinogenesis, and constituents in the diet, including dietary glucosinolate derivatives, have the potential to alter a number of these epigenetic events [18, 15, 26]. Although most research on the cellular effects of dietary glucosinolate derivatives has primarily focused on detoxifying enzyme effects, increasing evidence has demonstrated the chemopreventive effects of dietary glucosinolate derivatives on the regulation of silenced genes in cancer.…”

“…DNA methylation occurs at the 5′ position of cytosine residues within CpG dinucleotides through addition of a methyl group by DNA methyltransferases (DNMTs), which include DNMT1, DNMT3A and DNMT3B, leading to transcriptional silencing of tumor suppressors and other genes with important biological functions. Conversely, global hypomethylation causes genome instability and inappropriate activation of oncogenes and transposable elements [77, 78, 26]. In this context, dietary glucosinolate derivatives, such as SFN, PEITC and DIM, have been shown to inhibit the carcinogenic process, enhance xenobiotic metabolism, induce cell cycle arrest and apoptosis and affect the cancer epigenome in various human cancers and cancer mouse models, demonstrating relevance as chemopreventive agents [79, 13, 23].…”

“…Histone modifications have been broadly recognized as critically important triggers of gene silencing via post-translational modifications of histones at amino-terminal tails [26]. For example, the open chromatin state and gene activation is mediated by histone acetyltransferases (HATs), which transfer acetyl groups to the ε-amino group of lysine residues in histone tails, whereas the condensed chromatin state and the respective gene silencing is commonly regulated by HDAC enzymes, which remove histone acetyl groups by catalyzing their transfer to coenzyme A (CoA) [84, 26].…”

CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45

“…Many studies have shown that cellular mechanisms contribute to the overall cancer-prevention effects of these dietary phytochemicals [33]. Natural phytochemicals from certain plants have the capability to affect the epigenome and can also trigger sustained DNA damage and apoptosis induction.…”