Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management? (original) (raw)
Related papers
Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms
Biomedicine & Pharmacotherapy, 2022
Cancer is a leading cause of morbidity and mortality around the globe. Reactive oxygen species (ROS) play contradicting roles in cancer incidence and progression. Antioxidants have attracted attention as emerging therapeutic agents. Among these are flavonoids, which are natural polyphenols with established anticancer and antioxidant capacities. Increasing evidence shows that flavonoids can inhibit carcinogenesis via suppressing ROS levels. Surprisingly, flavonoids can also trigger excessive oxidative stress, but this can also induce death of malignant cells. In this review, we explore the inherent characteristics that contribute to the antioxidant capacity of flavonoids, and we dissect the scenarios in which they play the contrasting role as pro-oxidants. Furthermore, we elaborate on the pathways that link flavonoid-mediated modulation of ROS to the prevention and treatment of cancer. Special attention is given to the ROS-mediated anticancer functions that (-)-epigallocatechin gallate (EGCG), hesperetin, naringenin, quercetin, luteolin, and apigenin evoke in various cancers. We also delve into the structure-function relations that make flavonoids potent antioxidants. This review provides a detailed perspective that can be utilized in future experiments or trials that aim at utilizing flavonoids or verifying their efficacy for developing new pharmacologic agents. We support the argument that flavonoids are attractive candidates for cancer therapy.
Natural products for cancer prevention associated with Nrf2–ARE pathway
Food Science and Human Wellness, 2013
Cancer chemoprevention involves the application of natural or synthetic compounds to reduce the risk of cancer development. One of the most effective strategies for preventing human cancers might involve inducing phase II detoxifying enzymes and antioxidant enzymes via natural dietary compounds. The regulatory regions of these inducible genes encode the antioxidant response element (ARE). Nuclear factor-erythroid 2-related factor 2 (Nrf2), as a transcription factor, plays a key role in the expression of ARE-mediated genes. Similarly, Nrf2 performs an essential function in the up-regulation of these genes in response to oxidative stress and treatment with dietary phytochemicals. In this article, we discuss the current state of knowledge regarding the Nrf2/ARE pathway as a potential molecular target for cancer chemoprevention and its molecular regulation mechanisms, and highlight Nrf2/ARE inducers derived from natural products, which may be used as chemopreventive agents for cancer patients.
Pharmacology & therapeutics, 2013
Reactive metabolites from carcinogens and oxidative stress can drive genetic mutations, genomic instability, neoplastic transformation, and ultimately carcinogenesis. Numerous dietary phytochemicals in vegetables/fruits have been shown to possess cancer chemopreventive effects in both preclinical animal models and human epidemiological studies. These phytochemicals could prevent the initiation of carcinogenesis via either direct scavenging of reactive oxygen species/reactive nitrogen species (ROS/RNS) or, more importantly, the induction of cellular defense detoxifying/antioxidant enzymes. These defense enzymes mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against ROS/RNS and reactive metabolites of carcinogens. In addition, these compounds would kill initiated/transformed cancer cells in vitro and in in vivo xenografts via diverse anti-cancer mechanisms. These mechanisms include the activation of signaling kinase...
Nrf2-Target Approaches in Cancer Chemoprevention Mediated by Dietary Phytochemicals
Methods in Pharmacology and Toxicology, 2013
Cancer chemoprevention with natural phytochemical compounds is an emerging strategy to prevent, impede, delay, or cure cancer. This chapter reviews the basic methods used to study the cancer chemopreventive potential of dietary phytochemicals acting by activating the transcriptional factor, nuclear factorerythroid 2-related factor 2 (Nrf2 or NFE2L2), a basic-region leucine zipper (bZIP) transcription factor that regulates the expression of many phase II detoxifying/antioxidant enzymes. The Nrf2-target approaches in cancer chemoprevention comprise different methods including examining the Nrf2 signaling pathway, Nrf2-deficient tumor mouse models, pharmacokinetics (PK)/pharmacodynamics (PD) assessment, and epigenetic regulation.
Topics in current chemistry, 2013
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 S-transferases (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 anti-inflammatory signaling pathways to protect organisms against cellular damage caused by oxidative stress. In addition, carcinogenesis can be caused by epigen...
Journal of traditional and complementary medicine, 2013
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 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/detoxi...
International Journal of Molecular Sciences
Cancer is one of the leading causes of death worldwide. Chemotherapy and radiation therapy are currently providing the basis for cancer therapies, although both are associated with significant side effects. Thus, cancer prevention through dietary modifications has been receiving growing interest. The potential of selected flavonoids in reducing carcinogen-induced reactive oxygen species (ROS) and DNA damage through the activation of nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2)/antioxidant response element (ARE) pathway was studied in vitro. Dose-dependent effects of pre-incubated flavonoids on pro-carcinogen 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKAc)-induced ROS and DNA damage in human bronchial epithelial cells were studied in comparison to non-flavonoids. The most effective flavonoids were assessed for the activation of Nrf2/ARE pathway. Genistein, procyanidin B2 (PCB2), and quercetin significantly suppressed the NNKAc-induced ROS and DNA damag...
Flavonoid effects relevant to cancer
The Journal of …, 2002
Flavonoids, such as daidzein and genistein, present in dietary plants like soybean, have unique chemical properties with biological activity relevant to cancer. Many flavonoids and polyphenols, including resveratrol in red wine and epigallocatechin gallate in green tea, are known antioxidants. Some of these compounds have estrogenic (and antiestrogenic) activity and are commonly referred to as phytoestrogens. A yeastbased estrogen receptor (ER) reporter assay has been used to measure the ability of flavonoids to bind to ER and activate estrogen responsive genes. Recently, estrogenic compounds were also shown to trigger rapid, nongenomic effects. The molecular mechanisms, however, have not been completely detailed and little information exists regarding their relevance to cancer progression. As a preliminary step toward elucidating rapid phytoestrogen action on breast cancer cells, we investigated the effect of 17- estradiol (E 2), genistein, daidzein and resveratrol on the activation status of signaling proteins that regulate cell survival and invasion, the cell properties underlying breast cancer progression. The effect of these estrogenic compounds on the activation, via phosphorylation, of Akt/protein kinase B (Akt) and focal adhesion kinase (FAK) were analyzed in ER-positive and-negative human breast cancer cell lines. E 2 , genistein and daidzein increased whereas resveratrol decreased both Akt and FAK phosphorylation in nonmetastatic ER-positive T47D cells. In metastatic ER-negative MDA-MB-231 cells, all estrogenic compounds tested increased Akt and FAK phosphorylation. The inhibitory action of resveratrol on cell survival and proliferation is ER dependent. Therefore, all estrogenic compounds tested, including resveratrol, may exert supplementary ER-independent nongenomic effects on cell survival and migration in breast cancer cells. J. Nutr. 132: 3482S-3489S, 2002. KEY WORDS: • estrogen signaling • phytoestrogen • breast cancer progression • FAK activity • Akt activity • phosphorylation • antioxidant activity
Flavonoid-induced glutathione depletion: Potential implications for cancer treatment
Free Radical Biology and Medicine, 2006
Hydroxychalcones are naturally occurring compounds that continue to attract considerable interest because of their anti-inflammatory and antiangiogenic properties. They have been reported to inhibit the synthesis of the inducible nitric oxide synthase and to induce the expression of heme oxygenase-1. This study examines the mechanisms by which 2′,5′-dihydroxychalcone (2′,5′-DHC) induces an increase in cellular glutathione (GSH) levels using a cell line stably expressing a luciferase reporter gene driven by antioxidant-response elements (MCF-7/AREc32). The 2′,5′-DHC-induced increase in cellular GSH levels was partially inhibited by the catalytic antioxidant MnTDE-1,3-IP 5+ , suggesting that reactive oxygen species (ROS) mediate the antioxidant adaptive response. 2′,5′-DHC treatment induced phosphorylation of the c-Jun N-terminal kinase (JNK) pathway, which was also inhibited by MnTDE-1,3-IP 5+ . These findings suggest a ROS-dependent activation of the AP-1 transcriptional response. However, whereas 2′,5′-DHC triggered the NF-E2-related factor 2 (Nrf2) transcriptional response, cotreatment with MnTDE-1,3-IP 5+ did not decrease 2′,5′-DHCinduced Nrf2/ARE activity, showing that this pathway is not dependent on ROS. Moreover, pharmacological inhibitors of mitogen-activated protein kinase (MAPK) pathways showed a role for JNK and p38MAPK in mediating the 2′,5′-DHC-induced Nrf2 response. These findings suggest that the 2′,5′-DHC-induced increase in GSH levels results from a combination of ROS-dependent and ROS-independent pathways.
Applied Sciences
ROS, RNS, and carcinogenic metabolites generate excessive oxidative stress, which changes the basal cellular status and leads to epigenetic modification, genomic instability, and initiation of cancer. Epigenetic modification may inhibit tumor-suppressor genes and activate oncogenes, enabling cells to have cancer promoting properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that in humans is encoded by the NFE2L2 gene, and is activated in response to cellular stress. It can regulate redox homoeostasis by expressing several cytoprotective enzymes, including NADPH quinine oxidoreductase, heme oxygenase-1, UDP-glucuronosyltransferase, glutathione peroxidase, glutathione-S-transferase, etc. There is accumulating evidence supporting the idea that dietary nutraceuticals derived from commonly used fruits, vegetables, and spices have the ability to produce cancer chemopreventive activity by inducing Nrf2-mediated detoxifying enzymes. In this review, w...