Regulation of Antioxidant Response Element Pathways by Natural

Chapter 9

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Regulation of Antioxidant Response Element Pathways by Natural Chemopreventive Compounds 1

Woo-Sik Jeong and M i r a J u n

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Food Science Institute, School of Food and Life Science, College of Biomedical Science and Engineering, Inje University, 607 Obang-dong, Gimhae 621-749, Korea Department of Food Science, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901-8520

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Research indicates that protecting cells or tissues from carcinogens and carcinogenic metabolites through the induction of cellular defense enzymes, such as phase 2 detoxifying and antioxidant enzymes, is a method of chemoprevention that shows great promise. Antioxidant response element (ARE) is located in the promoter region of these defense genes and plays a key role in the induction of these enzymes. Many natural chemopreventive agents are known to induce ARE-mediated gene expression and regulate the upstream signalings involved in the A R E pathway.

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© 2007 American Chemical Society In Antioxidant Measurement and Applications; Shahidi, Fereidoon, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

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Cancer Chemoprevention Carcinogenesis is typically classified into three stages of initiation, promotion, and progression (7). Various natural and synthetic chemicals, the socalled chemopreventive agents, can interfere with these stages. Chemoprevention is defined as a cancer-preventive approach that utilizes natural or synthetic pharmacological agents to impede, arrest, or reverse carcinogenesis at its early stages (2). Natural compounds found in foods and edible plants have gained much attention as potential chemopreventive agents due to their relatively low toxicity, low cost, and easy availability as well as their general identity as health foods (3). Therefore, the use of natural compounds as chemopreventive agents could be one of the most probable strategies for cancer chemoprevention.

Induction of Cellular Defense Enzymes One of the most important cancer chemopreventive properties of natural compounds could be their ability to induce cellular defense enzymes, such as phase 2 detoxifying and antioxidant enzymes, which can protect cells and tissues against various endogenous and exogenous carcinogens and carcinogenic metabolites. Examples of these defense enzymes are glutathione S-transferase (GST), N A D ( P ) H quinone oxidoreductase 1 (NQOl), γ-glutamylcysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1).

N r f 2 / A R E Signaling Pathway The induction of these defense genes is mediated, at least in part, by the antioxidant response element (ARE) in the promoter region of these genes (4). Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap ' n ' collar (CNC) family of basic region-leucine zipper (bZIP) proteins, plays a key role in ARE-dependent gene expression. Upon exposure of cells to its inducers, such as oxidative stress and certain chemopreventive agents, it dissociates from Keap 1, translocates from the cytosol to the nucleus, binds to AREs and transactivates the cellular defense enzymes (5, 6). Nrf2/ARE pathway is of great interest as a potential molecular target for cancer prevention. Several natural compounds including isothiocyanates, diallyl sulfides, indoles, terpenes, and phenolic compounds, such as tea catechins and curcuminoids, have been reported to modulate Nrf2/ARE signaling pathways (7-14).

In Antioxidant Measurement and Applications; Shahidi, Fereidoon, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

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Naturally Occurring Potential Cancer Chemoprenventive Compounds Involved in NrC/ARE Pathways


Examples of natural chemopreventive compounds that have been studied include isothiocyanates, diallyl sulfides, tea catechins, curcuminoids, indoles and sesquiterpenes. The chemical structures of these compounds are illustrated in Figure 1.

AJlyl isothiocyanate

Parthenolide

Curcumin

Figure 1. The Structures of natural chemopreventive compounds involved in Nrf2/ARE pathways.


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Isothiocyanates Isothiocyanates are found mainly in cruciferous vegetables including broccoli, watercress, brussels sprouts, cabbage, and cauliflower (75). Glucosinolates are precursors of isothiocyanates in intact plant tissues. Upon physical stress followed by enzymatic reaction of plant-specific myrosinase or by intestinal microflora, they are converted to isothiocyanates such as sulforaphane, phenethyl isothiocyanate (PEITC), and allyl isothiocyanate (AITC) (16). Sulforaphane could be one of the most potent inducers of cellular defense enzymes. It induces mitogen activated protein kinases (MAPKs), Nrf2, A R E reporter gene activity, and phase 2 detoxifying and antioxidant enzymes such as N Q O l and HO-1 (9, 17, 13, 14). One possible mechanism for this induction is that sulforaphane disrupts the cytoplasmic complex between Keapl and Nrf2 by reacting with covalent bonds between the Nrf2-Keapl complex, that results in the release of Nrf2 to the nucleus and the activation of ARE-dependent genes (75). Increased stability of Nrf2 protein also accounts for the induction of cellular defense enzymes by sulforaphane (9, 14). PEITC is another promising isothiocyanate compound with cancer chemopreventive potential. It has been shown to dose-dependently activate ARE-reporter gene activity in a transiently transfected cell line model (19). In addition, co-transfection of Nrf2 and JNK1 together with PEITC treatment showed additional enhancement of the ARE-reporter activity. Overexpression of dominant-negative JNK1 suppressed Nrf2-induced ARE-reporter gene expression, suggesting a role of JNK1 in an upstream activation of Nrf2. Activation of JNKs by PEITC has also been implicated as an apoptotic mechanism induced by PEITC (20). Induction of Nrf2 and antioxidant enzyme HO-1 was observed when HepG2 cells were treated with AITC but their potency was less than those of sulforaphane and PEITC (9).

Diali} 1 Sulfides The allium family, including garlic, onion, and chive, contains a series of potential chemopreventive agents such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS). Induction of phase 2 detoxifying enzymes (GST, glutathione reductase, N Q O l and ferritin) has been reported in vitro and in vivo (21-23). A structure-activity relationship study with various organosulfides showed that D A T S is a very potent stimulator of A R E activation as well as nuclear accumulation of Nrf2 (8). It can also strongly induce expression of phase 2 detoxifying and antioxidant enzymes such as N Q O l , and HO-1 proteins. The third sulfur in the structure of the diallyl sulfides is proposed


122 to contribute to their bioactivities. In addition, allyl-containing sulfides were found to be more potent than propyl-containing sulfides. D A T S also activated M A P K s such as E R K , JNK, and p38 (8, 24).


Phenolic Compounds Phenolic compounds are found in almost all plants and a number of phenolic compounds have long been studied for their chemopreventive potential. However, their roles in cellular defense mechanisms, in particular their role in the Nrf2/ARE pathway, are not fully understood. O f phenolic compounds, those in green tea such as (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG), are well known antioxidants and their beneficial properties in cardiovascular disease and cancer are well documented (25, 26). E G C G and E C G have been found to induce ARE-mediated gene expression as well as M A P K s in HepG2 cells (27). In this study, the induction of A R E reporter gene appears to be structurally related to the 3-gallate group. Chlorogenic acid also increases the enzymatic activities of phase 2 enzymes such as GST and N Q O l through its stimulation of nuclear translocation of Nrf2 and subsequent induction of A R E in phase 2 genes (28). The PI-3 kinase pathway might be involved in the activation of Nrf2 translocation by chlorogenic acid. Curcumin, found in tumeric, and caffeic acid phenethyl ester (CAPE) present in propolis of honeybee hives are also potential natural chemopreventive agents. Curcumin and C A P E stimulate the expression of Nrf2 as well as A R E mediated phase 2 gene expression such as N Q O l and HO-1 in cell culture models (29, 30) Inactivation of the Nrf2-Keapl complex or involvement of p38 by these compounds are suggested.

Other Compounds Other natural compounds that possess chemopreventive properties through Nrf2/ARE pathway and subsequent induction of phase 2 detoxifying enzymes include terpenes and indole-3-carbinol (I3C). A sesquiterpene found in feverfew and parthenolide, stimulates ARE-reporter gene activity and potently induce expression of Nrf2 and HO-1 proteins in HepG2 cells (9). A recent study also indicates that parthenolide stimulates the binding activity of Nrf2 to A R E in HT22 cells (31). I3C is reported to retard the progression of aflatoxin B l induced carcinogenesis in animals at both the initiation and promotion stages. Treatment with I3C has shown significant induction of GST Yc2, aflatoxin B l


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aldehyde reductase and quinone reductase (32, 33). In HepG2 cells, I3C was a weak inducer of ARE-reporter gene activity and Nrf2 protein expression but had no effect on HO-1 protein expression (9). A n in vivo study using mice revealed that N Q O and GST enzyme activities in the small intestine of mice increased about 2-fold after feeding with a mixture of coffee diterpenes, cafestol and kahweol palmitate (77).

Acknowledgements This work was supported by a 2004 Inje University research grant.

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Regulation of Antioxidant Response Element Pathways by Natural

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