Cancer Letters

Cancer Letters

Volume 224, Issue 2, 28 June 2005, Pages 171-184
Cancer Letters

Mini-review
Nrf2 as a novel molecular target for chemoprevention

https://doi.org/10.1016/j.canlet.2004.09.042Get rights and content

Abstract

One of the rational and effective strategies for chemoprevention is the blockade of DNA damage caused by carcinogenic insult. This can be achieved either by reducing the formation of reactive carcinogenic species or stimulating their detoxification. A wide spectrum of xenobiotic metabolizing enzymes catalyze both phase I (oxidation and reduction) and phase II biotransformation (conjugation) reactions involved in carcinogen activation and/or deactivation. Several antioxidant-response element (ARE)-regulated gene products such as glutathione S-transferase, NAD(P)H:quinone oxidoreductase 1, UDP-glucuronosyltransferase, γ-glutamate cysteine ligase, and hemeoxygenase-1 are known to mediate detoxification and/or to exert antioxidant functions thereby protecting cells from genotoxic damage. The transcription of ARE-driven genes is regulated, at least in part, by nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2), which is sequestered in cytoplasm by Kelch-like ECH-associated protein 1 (Keap1). Exposure of cells to ARE inducers results in the dissociation of Nrf2 from Keap1 and facilitates translocation of Nrf2 to the nucleus, where it heterodimerizes with small Maf protein, and binds to ARE, eventually resulting in the transcriptional regulation of target genes. The Nrf2–Keap1–ARE signaling pathway can be modulated by several upstream kinases including phosphatidylinositol 3-kinase, protein kinase C, and mitogen-activated protein kinases. Selected Nrf2–Keap1–ARE activators, such as oltipraz, anethole dithiolethione, sulforaphane, 6-methylsulphinylhexyl isothiocyanate, curcumin, caffeic acid phenethyl ester, 4′-bromoflavone, etc. are potential chemopreventive agents. This mini-review will focus on a chemopreventive strategy directed towards protection of DNA and other important cellular molecules by inducing de novo synthesis of phase II detoxifying or antioxidant genes via the Nrf2–ARE core signaling pathway.

Introduction

Carcinogenesis, a multistage process that involves molecular and cellular alterations, largely consists of three separate, but closely linked stages—tumor initiation, promotion and progression [1], [2], [3]. Initiation is a rapid and irreversible process that involves a chain of extracellular and intracellular events. These include the initial uptake of or exposure to a carcinogenic agent, its distribution and transport to organs and tissues where metabolic activation and detoxification can occur, and the covalent interaction of reactive species with target-cell DNA, leading to genotoxic damage. In contrast to initiation, tumor promotion is recognized as a relatively lengthy and reversible process in which actively proliferating preneoplastic cells accumulate. Progression, the final stage of neoplastic transformation, involves the growth of a tumor with invasive and metastatic potential. One of the rational and effective approaches to control cancer is the inhibition, reversal or delay of genetic and epigenetic events that result in neoplastic transformation of cells [4], [5], [6], [7], [8]. The term ‘chemoprevention’, first coined by Michael Sporn in the mid-1970s, refers to the use of relatively non-toxic chemical substances either of natural or synthetic origin to impede, arrest or reverse carcinogenesis in early stages [9]. Chemoprevention has been successfully achieved in numerous in vitro as well as in vivo studies over past 25 years, and has been validated in several human intervention trials [4], [7].

According to the conventional classification originally proposed by Lee Wattenberg, most chemopreventive agents can be broadly divided into two main categories—blocking agents and suppressing agents [10], [11]. Blocking agents prevent carcinogens from reaching the target sites, undergoing metabolic activation or subsequently interacting with crucial cellular macromolecules, such as DNA, RNA, and proteins [1]. Mechanistically diverse classes of compounds, which reduce formation and metabolic activation of carcinogens, trap and inactivate ultimate electrophilic carcinogens, or facilitate their elimination from the body [12], act as blocking agents. Suppressing agents, on the other hand, inhibit the premalignant and malignant transformation of initiated cells during the stage of promotion and progression, respectively. Actions of suppressing agents include inactivation of oncogenes, activation of tumor suppressor genes, inhibition of angiogenesis, and induction of apoptosis or terminal differentiation [11], [13]. One of the plausible mechanisms by which blocking agents impart their chemopreventive activity is the induction of a set of detoxification and antioxidant enzymes through the activation of intracellular signaling mediated by nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). This mini-review will focus on the chemopreventive strategy directed towards protection of DNA and other important intracellular macromolecules by inducing de novo synthesis of phase II detoxification or antioxidant genes via the antioxidant-response element (ARE)–Nrf2 core signaling pathway.

Section snippets

The induction of detoxification and antioxidant genes as prime basis of chemoprevention

The blocking of oncogenic insult-induced genotoxic damage constitutes the first degree prevention of cancer. This can be achieved either by reducing the formation of reactive carcinogenic species or stimulating their detoxification. Many xenobiotic metabolizing enzymes are involved in both phase I (oxidation and reduction) and phase II biotransformation (conjugation) reactions [14]. In general, carcinogen activation takes place primarily during phase I metabolism for which cytochrome P450

Role of Nrf2 signaling in ARE-mediated gene expression

When cells are under stressful condition, certain members of the helix-loop-helix basic leucine zipper (bZIP) family of transcription factors—such as Nrf, Jun, Fos, Fra, Maf and Ah receptor—heterodimerize and bind to the ARE sequence to induce transcription of phase II enzymes [13], [29]. A role of Nrf2 in the regulation of ARE-mediated gene expression has been shown in studies utilizing Nrf2-null mice [29]. Nrf2, a 66-kDa protein, have originally been found to interact with the NF-E2 DNA

Selected Nrf2–Keap1-ARE inducers as potential chemopreventive agents

Accumulating evidence supports that Nrf2-mediated activation of ARE, or more recently electrophile-responsive element (EpRE), is a central part of molecular mechanisms governing the protective function of phase II detoxification and antioxidant enzymes against chemical carcinogenesis and oxidative stress. A wide variety of dietary and synthetic compounds that function as potent inducers of ARE-regulated gene expression have been shown to exert chemopreventive activities. Examples are oltipraz,

Conclusion

Recent efforts to unravel the molecular mechanisms of tumor biology have provided a novel strategy for cancer prevention, termed chemoprevention that is based on stage-specific intervention of multistage carcinogenesis. Since phase II xenobiotic metabolizing enzymes are responsible for elimination or inactivation of carcinogens and other toxicants, it would be a rational chemoprevention approach to stimulate or facilitate carcinogen detoxification by augmenting both expression and activity of

Acknowledgements

This work was supported by a grant from the National Research Laboratory fund (to Y.-J. Surh) provided by KISTEP, Ministry of Science and Technology, Republic of Korea. The authors acknowledge Joydeb K. Kundu for critical reviews and editorial assistance of the manuscript.

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