Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management?

Abstract

The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cell signaling mechanism in maintaining redox homeostasis in humans. The role of dietary flavonoids in activating Nrf2/ARE in relation to cancer chemoprevention or cancer promotion is not well established. Here we summarize the dual effects of flavonoids in cancer chemoprevention and cancer promotion with respect to the regulation of the Nrf2/ARE pathway, while underlying the possible cellular mechanisms. Luteolin, apigenin, quercetin, myricetin, rutin, naringenin, epicatechin, and genistein activate the Nrf2/ARE pathway in both normal and cancer cells. The hormetic effect of flavonoids has been observed due to their antioxidant or prooxidant activity, depending on the concentrations. Reported in vitro and in vivo investigations suggest that the activation of the Nrf2/ARE pathway by either endogenous or exogenous stimuli under normal physiological conditions contributes to redox homeostasis, which may provide a mechanism for cancer chemoprevention. However, some flavonoids, such as luteolin, apigenin, myricetin, quercetin, naringenin, epicatechin, genistein, and daidzein, at low concentrations (1.5 to 20 µM) facilitate cancer cell growth and proliferation in vitro. Paradoxically, some flavonoids, including luteolin, apigenin, and chrysin, inhibit the Nrf2/ARE pathway in vitro. Therefore, even though flavonoids play a major role in cancer chemoprevention, due to their possible inducement of cancer cell growth, the effects of dietary flavonoids on cancer pathophysiology in patients or appropriate experimental animal models should be investigated systematically.

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

“…These observations were reproducibly obtained in four independent experiments and further analyses of the data by densitometry revealed that the silencing of NQO2 slightly but significantly augmented the basal autophagic flux in HepG2 cells, beside preventing further LC3-II induction in response to flavones ( Figure 3 B). In addition, we observed a reproducible induction of NQO2 expression by luteolin and apigenin ( Figure 3 C), which might reflect an ARE-mediated transcriptional stimulation of NQO2 promoter by NRF2, which is a well-known effect induced by flavones on ARE-regulated phase II and antioxidant enzymes [ 43 , 44 ].…”

High Resolution Mass Spectroscopy-Based Secondary Metabolite Profiling of Nymphaea nouchali (Burm. f) Stem Attenuates Oxidative Stress via Regulation of MAPK/Nrf2/HO-1/ROS Pathway

“…Multiple lines of evidence recommend that polyphenolics, such as protocatechuic acid, vanillic acid, gallic acid, naringenin, 5- O -caffeoylquinic acid, catechin, taxifolin, and vicenin-2 have the capability to augment the endogenous antioxidant system, leading to cellular protection from oxidative stress [ 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Therefore, it is hypothesized that the augmentation of first-line antioxidant enzymes by NNSE, resulting from an abundance of phenolics and flavonoids, may contribute to the beneficial effects of NNSE against oxidative stress.…”

Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy

“…Hesperetin has been shown to attenuate damage induced by hydrogen peroxide via direct radical scavenging and by enhancing the antioxidant response via ERK/Nrf2-mediated induction of HO-1 [198]. In diabetic rats, antioxidant, anti-inflammatory, and anti-angiogenic properties of hesperetin have been reported [199]. Hesperetin significantly attenuated oxidative stress, lipid peroxidation, and ROS production in mouse brains with Aβ-induced neurodegeneration.…”

“…Interestingly, CGA protected against acute liver injury in animal models via activation of the Nrf2 pathway and inhibition of the NLRP3 inflammasome [186,187]. -ERK/Nrf2 Induction-ER stress protection -NF-kB modulation [198][199][200][201][202][203][204][205][206]…”