Simultaneous Activation of Nrf2 and Elevation of Dietary and Endogenous Antioxidant Chemicals for Cancer Prevention in Humans

Despite extensive studies in cancer prevention, the incidence of cancer is increasing. We review studies that have identified several biochemical and genetic defects as well as potential carcinogens in the diet, environmental factors, and lifestyle-related habits. Two of the biochemical abnormalities increased oxidative stress and chronic inflammation, and chronic exposure to carcinogens and mutagens play a significant role in the initiation of multistage carcinogenesis. Therefore, attenuation of these biochemical defects may be useful in reducing the incidence of cancer. Activation of the transcriptional factor called nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which enhances the levels of antioxidant enzymes and phase-2-detoxifying enzymes by complex mechanisms, may be one of the ways to reduce oxidative stress and chronic inflammation. Antioxidant enzymes destroy free radicals by catalysis, whereas phase-2-detoxifying enzymes remove potential carcinogens by converting them to harmless compounds for elimination from the body. However, increasing the levels of antioxidant enzymes by activating Nrf2 may not be sufficient to decrease oxidative stress and chronic inflammation optimally, because antioxidant chemicals, which are decreased in a high oxidative environment, must also be elevated. This review discusses the regulation of activation of Nrf2 and proposes a hypothesis that an elevation of the levels of antioxidant enzymes and dietary and endogenous antioxidant chemicals simultaneously may reduce the incidence of cancer by decreasing oxidative stress and chronic inflammation. The levels of antioxidant chemicals can be increased by supplementation, but increasing the levels of antioxidant enzymes requires activation of Nrf2 by reactive oxygen species (ROS)-dependent and-independent mechanisms. Several phytochemicals and antioxidant chemicals that activate Nrf2 have been identified. This review also describes clinical studies on antioxidants in cancer prevention that have produced inconsistent results. It discusses the possible reasons for the inconsistent results and proposes criteria that should be included in the experimental designs of future clinical studies to obtain consistent results. Key teaching points: •Reducing oxidative stress and chronic inflammation optimally requires an elevation of the levels of antioxidant enzymes and phase-2-detoxifying enzymes as well as dietary and endogenous antioxidant chemicals. •How the levels of antioxidant enzymes and phase-2-detoxifying enzymes are regulated by a nuclear transcriptional factor Nrf2. •How the activation and transcription of Nrf2 is regulated. •Identification of antioxidants that activate Nrf2 by ROS-dependent and-independent mechanisms, those that destroy free radicals by scavenging, and those that exhibit both functions. •Possible reasons for the inconsistent results produced by the previous clinical studies on antioxidants in cancer prevention. •The criteria that should be included in the experimental designs of future clinical studies on antioxidants in cancer prevention in high-risk populations to obtain consistent results.