Nrf2 and cancer chemoprevention by phytochemicals

A cluster of research reports has appeared during the last few years looking at  mechanisms through which substances rich in phytochemicals (e.g. coffee, chocolate, turmeric, olive oil, broccoli, red hot peppers, green tea, garlic, blueberries, rosemary, oregano, sage) are cancer-preventative. While these foods have been studied for many years a new focal point has been moving to center stage – study of what these substances are doing in terms of gene expression as a key to understanding their therapeutic value.  The 2005 paper Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects articulates this emerging viewpoint.  “The process of cancer development (carcinogenesis leading to advanced metastasized cancers) in humans generally takes many years through initiation, promotion and progression. Because advanced metastasized cancers are almost impossible to treat, cancer chemoprevention for the control and containment of early cancer development is highly desirable. Recent studies have provided strong evidence that many daily-consumed dietary compounds possess cancer-protective properties that might interrupt the carcinogenesis process. These properties include the induction of cellular defense detoxifying and antioxidant enzymes, which can protect against cellular damage caused by environmental carcinogens or endogenously generated reactive oxygen species. These compounds can also affect cell-death signaling pathways, which could prevent the proliferation of tumor cells.”

One master activator of antioxidant and anticancer genes appears to be Nuclear factor-erythroid-2-related factor 2 (Nrf2). The sequence of events involved in phytochemical chemoprevention mediated by Nrf2 is complex and is summarized in the 2008 publication Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.  “A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities.” For those of you who have a taste for molecular biology, that document goes on to explain “Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5′-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed.”

Two signaling pathways frequently mentioned in this blog, the MAPK/ERK and PI3K/Akt pathways, appeared to be involved as pointed out in the 2009 publication Salvia Fruticosa, Salvia Officinalis, and Rosmarinic Acid Induce Apoptosis and Inhibit Proliferation of Human Colorectal Cell Lines: The Role in MAPK/ERK Pathway. “In the present study, the antiproliferative and proapoptotic effects of water extracts of Salvia fruticosa (SF) and Salvia officinalis (SO) and of their main phenolic compound rosmarinic acid (RA) were evaluated in two human colon carcinoma-derived cell lines, HCT15 and CO115, which have different mutations in the MAPK/ERK and PI3K/Akt signalling pathways. — Our results show that SF, SO, and RA induce apoptosis in both cell lines, whereas cell proliferation was inhibited by the two sage extracts only in HCT15. SO, SF, and RA inhibited ERK phosphorylation in HCT15 and had no effects on Akt phosphorylation in CO115 cells. The activity of sage extracts seems to be due, at least in part, to the inhibition of MAPK/ERK pathway.” 

Phytochemical cancer chemoprevention may involve a number of additional pathways besides Nrf2 .  A number of phytosubstances are powerful anti-inflammatories for example and this may play a role in their control of cancer.  Bromelain, ginger, curcumin, aswagandah and boswellia are in this category.  Inhibition of TNFalpha-activated NF-kappaB signaling may also play an important role in preventing cancer activation as pointed out in my treatise.  A number of herbal substances that are NF-kappaB inhibitors are in my combined anti-aging firewall. 

The use of herbal substances for cancer chemoprevention is receiving a lot of attention, especially now that the chains of molecular activities initiated by these traditional substances are starting to be understood.  The 2007 publication Chemopreventive herbal anti-oxidants: current status and future perspectives states “Cancer chemoprevention is fast becoming a lucrative approach for controlling cancer. Carcinogenesis being a complex multi-step, multi-factorial process, a number of chemopreventive interventions can be employed. These strategies are generally directed against two broad events of carcinogenesis viz., initiation and promotion/progression. Anti-initiation interventions principally involve inhibition of carcinogen activation, scavenging of free radicals and reactive carcinogen metabolites along with enhanced detoxification of carcinogens by modulating cellular metabolism. Anti-promotion strategies involve attenuation of enhanced cellular proliferation along with induction of cellular apoptosis and differentiation. Dietary agents or herbal anti-oxidants due to low toxicity and relative safety are promising chemopreventive agents.” 

Other publications on cancer chemoprevention include Comprehensive review of cancer chemopreventive agents evaluated in experimental carcinogenesis models and clinical trials, Chemopreventive effects of natural dietary compounds on cancer development,  Organosulfur compounds in cancer chemoprevention, Cancer prevention by natural compounds, Cruciferous vegetables and cancer prevention, Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis, Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Following the hyperlinks to and from these publications will lead to many more.Those of you familiar with my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY  know that I suggest consumption of phytochemical-rich foods like blueberries, walnuts, chocolate and green tea and suggests taking a substantial number of phytosubstance supplements including resveratrol, curcumin, boswellia, ashwagandah, pycnogenol, green tea extract, olive leaf extract, lycopene, allicin and  OPC grape seed extract.  The blog post Phytochemicals – focus on caffeic acid  looks at one important phytochemical in depth, the one that is in coffee. And the post Health and longevity benefits of dark chocolate looks at another of my favorite phytosubstances.

Another action of Nrf2 is protection of arteries from fluid sheer stress generated by blood flow.  The 2009 publication Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells describes how sheer stress induces nuclear translocation of Nrf2 which restores laminar flow.  The paper concludes “Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.”  Several other papers have been written on this effect  such as the 2007 paper Shear stress stabilizes NF-E2-related factor 2 and induces antioxidant genes in endothelial cells: role of reactive oxygen/nitrogen species.

For a personal story from my childhood involving two phytosubstances and cancer, see the blog post Red wine, hot peppers and my uncle Gigi.