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Natural Phytochemical Nrf2 Activators for Chemoprevention

Dr. Hank Liers here considers mechanisms involved in the activation of transcription factor Nrf2. Nrf2 is encoded by the NFE2L2 gene. Nrf2 can induce expression of genes encoding for antioxidant enzymes. Thus, it contributes to regulation of oxidative stress. Dr. Liers' interest regards use of natural phytochemical Nrf2 activators for improving health. Also, see his previous post, "New Directions for Preventing Free-Radical Damage" (06.07.12).


Dr. Hank Liers, PhD nrf2 activatorsDespite progress in the early detection and treatment of cancer, overall mortality rates for most cancers of epithelial origin have not declined during the past three decades. Consequently, in recent years attention has been directed to cancer prevention.

Carcinogenesis can be viewed as a multistep process in which the genes controlling proliferation, differentiation, and apoptosis are transformed and altered under selective environmental pressures.

Tumor development involves three distinct, yet closely linked, phases: initiation, promotion, and progression. The initiation phase is a rapid and irreversible event that occurs when a normal cell is exposed to a carcinogenic event. Frequently, unrepairable or misrepaired DNA damage happens in the initiation phase.

Promotion and progression processes are relatively longer processes than the initiation stage, and are considered reversible. Using various animal cancer models, scientists found that all three cancer development stages can be intervened by treatment with natural (or synthetic) chemicals.

Epidemiological and population studies also establish a close relationship between incidence of cancer and consumption of certain types of food.

The term “chemoprevention” was first coined in 1976 by Michael Sporn, when he referred to prevention of malignancy development by vitamin A and its synthetic analogs. Since then, chemoprevention has been adopted as one of the major tactics to modulate the process of carcinogenesis. Many research studies have proven this strategy is effective in reducing the incidence of cancer in well-defined high-risk groups.

Chemoprevention is by definition the use of natural (or pharmacologic) agents to inhibit the development of invasive cancer. The chemicals with a cancer preventive activity are referred to as chemopreventive agents. A chemopreventive agent can inhibit carcinogenesis either by blocking the DNA damage at initiation stage or by arresting or reversing the processes at promotion and progression stages. Most of the chemical substances used in cancer chemoprevention studies are natural phytochemicals found in food.

On the basis of the inhibition stages, chemopreventive agents have been classified into two categories, namely blocking agents and suppressing agents. Blocking agents act by preventing carcinogens from reaching the target sites, from undergoing metabolic activation, or from subsequently interacting with crucial cellular macromolecules such as DNA, RNA, and proteins at initiation stages.

Suppressing agents, on the other hand, inhibit the malignant transformation of initiated cells at either the promotion or the progression stage. Some agents may work on all three stages of carcinogenesis, and are hence classified into both categories.


Many different animal models and cancer cell lines have been used to evaluate the chemopreventive values of phytochemicals, and have led to the discovery of new classes of chemopreventive agents. These agents include isothiocyanates (such as sulforaphane) from cruciferous vegetables, polyphenols from green and black tea, curcuminoids (from turmeric root), stilbenes such as resveratrol (from giant knotweed plant), flavonoids such as quercetin, and anthocyanidins (from many fruits and soybeans).

Progress also has been made in understanding the mode of action of newly identified chemopreventive agents. Exposure to the chemopreventive agents produces certain level of reactive oxygen species (ROS) or electrophiles, and causes mild oxidative/electrophilic stresses in cells.

Ultimate Protector - nrf2 activator

Such mild oxidative stresses are sufficient to initiate the signaling pathways that, in turn, can activate a variety of cellular events, such as induction of phase II detoxification enzymes and antioxidant enzymes, expression of tumor-suppressor genes, and inhibition of cell proliferation and angiogenesis.

In order to survive under a variety of environmental or intracellular stresses, our cells have developed highly efficient protective mechanisms to protect themselves from oxidative or electrophilic challenges. Proteins that comprise phase II detoxification and antioxidant enzymes provide an enzymatic line of defense against reactive oxygen species. These enzymes include superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione S-transferase (GST), and glutamate cysteine ligase.

Induction of phase II and antioxidant enzymes are regulated at the DNA/gene level by antioxidant responsive element (ARE). ARE-mediated gene expression plays a central role in the cellular defense against cellular oxidative damage.

Experimental evidence supports the view that induction of ARE-mediated cytoprotective enzymes is a critical and sufficient mechanism to enable protection against carcinogenesis provoked by environmental and endogenous insults.

One of the key ARE-binding transcription factors is Nrf2. Induction of cytoprotective enzymes in response to ROS, electrophiles, and chemopreventive agents is a cellular event that is highly dependent on Nrf2 protein.


By activating Nrf2 signaling, chemopreventive agents can increase cellular detoxification and antioxidant enzymes, thereby enhancing removal of reactive carcinogens and blocking carcinogenesis. This hypothesis has been tested in many studies.

For example, a study with sulforaphane (an isothiocyanate present abundantly in cruciferous vegetables) has shown that oral administration of this phytochemical could effectively block benzo[a]pyrene-induced forestomach tumors in mice. This protective effect was abrogated in mice that could not produce Nrf2, supporting a critical role of phase II detoxification and antioxidant enzymes in the prevention of carcinogenesis by chemopreventive agents.

Nrf2 is normally bound in the cytoplasm of cells to a protein called KEAP1. However, when an appropriate phytochemical agent attaches to a kinase receptor on the cell wall a phosphate group is released that causes the Nrf2 to be released. The Nrf2 then migrates into the cell nucleus and causes an antioxidant enzyme, such as SOD, to be released. This endogenously produced enzyme then can protect against ROS, electrophiles, and chemopreventive agents.

In practice, it has been found that a combination of multiple polyphenols works significantly better than single ingredients at activating Nrf2. In fact, in one experiment it was found that a combination of five ingredients all known to be Nrf2 activators was 18 times more effective than any single ingredient. Furthermore, it was found that this combination of five ingredients  increased levels of SOD by 30% and catalase by 56% after 120 days.


In view of the above information, we have developed an exceptional formula designed to maximize activation of Nrf2 in the body. This new product is ULTIMATE PROTECTOR. It is among the most advanced, natural Nrf2 activator formula on the market today.

We include a broad range of Nrf2 activators in ULTIMATE PROTECTOR. These activators source from a wide variety of freeze-dried and concentrated fruits, vegetables, and herbs. These include Wild Blueberry, Wild Bilberry, Acai, Black Currant Extract, Sweet Cherry, Raspberry, Elderberry, Blackberry, Aronia, Black Soybean Hull Extract, Blue Corn, CoffeeBerry, Curcumin (standardized extract with 95% curcuminoids from Turmeric), Glutathione (reduced), Trans-Resveratrol (98% from Giant Knotweed),Grape Seed, Cranberry, Tart Cherry, Prune, Raspberry Seed, Strawberry, Quercetin, Broccoli, Broccoli Sprouts, Tomato, Kale, Carrot, Brussels Sprouts, Onion, and Spinach.

Phytochemicals provided by the array of freeze-dried and concentrated fruits, vegetables, and herbs in the formula include: Polyphenols, Phenolic acids, Anthocyandins, Sulforaphane, Glucosinolates, Lutein, Lycopene, Beta Carotene, Chlorogenic acid, Ellagic acid, Quercetin, Quinic acid, Proanthocyanidins, Trans-Resveratrol, Ferulic acid, Caffeic acid, and Polysaccharides.

In addition to these Nrf2 activators (above), ULTIMATE PROTECTOR contains an extremely broad array of plant based antioxidants from the same sources described above, as well as from non-GMO Vitamin C from cassava / tapioca. All ingredients in this product have been used in chemoprevention protocols, as well as in protocols aimed at preventing free-radical damage in the body.

Ultimate Protector is now available on the HPDI website!



"Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells."  Am J Physiol Lung Cell Mol Physiol 294: L478–L488, 2008.

"Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals." Planta Med. 2008 Oct; 74(13): 1526–39. Epub 2008 Oct 20.

"Nrf2: a potential molecular target for cancer chemoprevention by natural compounds." Antioxid Redox Signal. 2006 Jan–Feb; 8(1–2):99–106.

"Cancer chemoprevention by phytochemicals: potential molecular targets, biomarkers and animal models." Acta Pharmacol Sin. 2007 Sep; 28(9): 1409–21.

"Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells." Acta Pharmacol Sin. 2007 Apr; 28(4): 459–72.

"Anticarcinogenesis by dietary phytochemicals: cytoprotection by Nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-kappa B and AP-1 in abnormal cancer cells." Food Chem Toxicol. 2008 Apr; 46(4): 1257–70. Epub 2007 Sep 15.

"Signal transduction events elicited by cancer prevention compounds." Mutat Res. 2001 Sep 1; 480–481: 231–41.

"Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention." Toxicology. 2010 Dec 5; 278(2): 229–41. Epub 2009 Oct 20.

"NF-kappa B and Nrf2 as potential chemopreventive targets of some anti-inflammatory and antioxidative phytonutrients with anti-inflammatory and antioxidative activities." Asia Pac J Clin Nutr. 2008; 17 Suppl 1:269–72.

"Regulation of NF-E2-Related Factor 2 Signaling for Cancer Chemoprevention: Antioxidant Coupled with Antiinflammatory." Antioxid Redox Signal. 2010 Dec 1; 13(11): 1679–98. Epub 2010 Aug 17.

"Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention." AAPS J. 2010 Mar; 12(1): 87–97. Epub 2009 Dec 15.

"Dietary chemopreventive compounds and ARE/EpRE signaling." Free Radic Biol Med. 2004 Jun 15; 36(12): 1505–16.

 "Multiple molecular targets in cancer chemoprevention by curcumin." AAPS J. 2006 Jul 7; 8(3): E443–9.


Ultimate Protector™

Questions & Answers about Ultimate Protector

Ultimate Protector Design Considerations – by Dr. Hank Liers

The Amazing Healing Potential of Natural Nrf2 Activators – by Dr. Hank Liers

Ultimate Protector™: First Impressions  – by Dr. Hank Liers

Ultimate Protector™ ORAC5.0™ Test Results  – by Dr. Hank Liers

Preventing Free-Radical Damage Using Ultimate Protector™ – by Dr. Hank Liers

New Directions for Preventing Free-Radical Damage  – by Dr. Hank Liers

Description and Comparison of ORAC Tests for Well Known Plant Ingredients and Ultimate Protector™ – by Dr. Hank Liers

Ultimate Protector and the Role of Foundational Supplements for Health – by Fred Liers, PhD

Ultimate Protector flyer (.pdf)

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