Cancer Chemopreventive Role of Dietary Terpenoids by Modulating Keap1-Nrf2-ARE Signaling System—A Comprehensive Update

ROS, RNS, and carcinogenic metabolites generate excessive oxidative stress, which changes the basal cellular status and leads to epigenetic modification, genomic instability, and initiation of cancer. Epigenetic modification may inhibit tumor-suppressor genes and activate oncogenes, enabling cells to have cancer promoting properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that in humans is encoded by the NFE2L2 gene, and is activated in response to cellular stress. It can regulate redox homoeostasis by expressing several cytoprotective enzymes, including NADPH quinine oxidoreductase, heme oxygenase-1, UDP-glucuronosyltransferase, glutathione peroxidase, glutathione-S-transferase, etc. There is accumulating evidence supporting the idea that dietary nutraceuticals derived from commonly used fruits, vegetables, and spices have the ability to produce cancer chemopreventive activity by inducing Nrf2-mediated detoxifying enzymes. In this review, we discuss the importance of these nutraceuticals in cancer chemoprevention and summarize the role of dietary terpenoids in this respect. This approach was taken to accumulate the mechanistic function of these terpenoids to develop a comprehensive understanding of their direct and indirect roles in modulating the Keap1-Nrf2-ARE signaling system.

The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism

The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers.

Curcumin Protects Skin against UVB-Induced Cytotoxicity via the Keap1-Nrf2 Pathway: The Use of a Microemulsion Delivery System

Curcumin was found to be beneficial in treating several skin pathologies and diseases, providing antioxidant protection due to its reducing properties and its electrophilic properties (the ability to activate the Nrf2 pathway and induce phase II cytoprotective enzymes). Nevertheless, clinical applications of curcumin are being hampered by its insufficient solubility, chemical instability, and poor absorption, leading to low efficacy in preventing skin pathologies. These limitations can be overcome by using a nanotechnology-based delivery system. Here, we elucidated the possibility of using curcumin encapsulated in a microemulsion preserving its unique chemical structure. We also examined whether curcumin microemulsion would reduce UVB-induced toxicity in skin. A significant curcumin concentration was found in the human skin dermis following topical application of a curcumin microemulsion. Moreover, curcumin microemulsion enhanced the reduction of UV-induced cytotoxicity in epidermal cells, paving the way for other incorporated electrophiles in encapsulated form protecting skin against stress-related diseases.

Molecular effects of cancer-associated somatic mutations on the structural and target recognition properties of Keap1

Kelch-like ECH-associated protein 1 (Keap1) plays an important regulatory role in the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent oxidative stress response pathway. It functions as a repressor of Nrf2, a key transcription factor that initiates the expression of cytoprotective enzymes during oxidative stress to protect cells from damage caused by reactive oxygen species. Recent studies show that mutations of Keap1 can lead to aberrant activation of the antioxidant pathway, which is associated with different types of cancers. To gain a mechanistic understanding of the links between Keap1 mutations and cancer pathogenesis, we have investigated the molecular effects of a series of mutations (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C and G476R) on the structural and target recognition properties of Keap1 by using nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD) and isothermal titration calorimetry (ITC). Depending on their locations in the protein, these mutations are found to exert differential effects on the protein stability and target binding. Together with the proposed hinge-and-latch mechanism of Nrf2–Keap1 binding in the literature, our results provide important insight into the molecular affect of different somatic mutations on Keap1’s function as an Nrf2 repressor.

Sulforaphane Attenuates Gentamicin-Induced Nephrotoxicity: Role of Mitochondrial Protection

Sulforaphane (SFN), an isothiocyanate naturally occurring in Cruciferae, induces cytoprotection in several tissues. Its protective effect has been associated with its ability to induce cytoprotective enzymes through an Nrf2-dependent pathway. Gentamicin (GM) is a widely used antibiotic; nephrotoxicity is the main side effect of this compound. In this study, it was investigated if SFN is able to induce protection against GM-induced nephropathy both in renal epithelial LLC-PK1 cells in culture and in rats. SFN prevented GM-induced death and loss of mitochondrial membrane potential in LLC-PK1 cells. In addition, it attenuated GM-induced renal injury (proteinuria, increases in serum creatinine, in blood urea nitrogen, and in urinary excretion on N-acetyl-β-D-glucosaminidase, and decrease in creatinine clearance and in plasma glutathione peroxidase activity) and necrosis and apoptosis in rats. The apoptotic death was associated with enhanced active caspase-9. Caspase-8 was unchanged in all the studied groups. In addition, SFN was able to prevent GM-induced protein nitration and decrease in the activity of antioxidant enzymes catalase and glutathione peroxidase in renal cortex. In conclusion, the protective effect of SFN against GM-induced acute kidney injury could be associated with the preservation in mitochondrial function that would prevent the intrinsic apoptosis and nitrosative stress.