Chapter 9 - Role Phytochemicals Play in the Activation of Antioxidant Response Elements (AREs) and Phase II Enzymes and Their Relation to Cancer Progression and Prevention

Abstract

Abstract Chemoprevention can be defined as a means of controlling cancer in which the incidence of the disease can be entirely prevented, slowed down, or reversed. Chemoprevention is acquiring great attention because it is a cost-effective alternative to cancer treatment, such as chemotherapy or radio-therapeutic programs, which should reduce the burden on local and global economies. There is increasing interest in studying the chemoprevention potentiality of natural compounds against cancer as a result of the reduced cancer risk in people who consume high amounts of phytochemicals in their diet. Chemoprevention may involve the interruption or reversal of the initiation and progression of the disease by setting targets with the goal of preventing end stage invasiveness and metastasis. The initiation stage of cancer can be stopped by preventing reactive oxygen species and/or carcinogen activity (i.e., scavenging free radicals or trapping carcinogens) or by inhibiting their metabolic activation, thereby suppressing their interaction with cellular macromolecular targets, such as DNA, RNA, and proteins. This can be achieved by inducing of a set of phase II detoxifying and antioxidant enzymes, such as the chemopreventive marker NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase (HO-1). NQO1 is a ubiquitous flavoenzyme that plays a crucial role in protecting cells from endogenous and exogenous oxidative stressors by catalyzing two- and four-electron reductions of these substrates to their hydroquinone forms. The expression of NQO1 in different tissues is regulated by antioxidant response elements (AREs) under both basal and oxidative stress conditions. NQO1 is known to be regulated by nuclear factor erythroid-derived related factor 2 (Nrf2), which belongs to the basic leucine zipper transcription factor family, and binds to AREs, leading to the expression of many cytoprotective and antioxidant genes. Since Nrf2 binds to AREs and regulates the expression and induction of NQO1, Nrf2 knockout causes a reduction in the constitutive expression of NQO1 and impairs its induction. Several vegetables and fruits, including blueberries, cocoa beans, cabbage, broccoli, and cauliflower, are among the most protective agents against cancer. This is specifically due to their high content of active phytochemicals, such as sulforaphanes, isothiocyanates, polyphenols, and flavonoids. Upon entering cells these chemicals can directly counteract free radicals and induce electrophilic stress signals that trigger proteins linked to diverse cellular signaling pathways. This capability involves activation of the NQO1 gene and other phase II detoxification genes by activating the Nrf2/Kelch-like ECH-associated protein (Keap1) complex system. This chapter reports the chemopreventive effect of dietary components or their phytochemicals by activating the Nrf2–Keap1/ARE pathway and inducing NQO1.