~ What Is Nuclear Factor-Kappa Beta? Part 2 - Nutrients That Inhibit NFkB

Nutrients That Inhibit NFkB

The search is on for safe, effective inhibitors of NFkB. One of the most exciting features of the explosion of NFkB research is that it sheds new light on the mechanisms of many familiar nutrients.

Health-conscious people are quite familiar with how antioxidants, vitamins, minerals, and essential nutrients such as omega-3 fatty acids can maintain health and prevent disease. It is becoming increasingly clear that many such compounds exert some of their beneficial effects through interactions with the NFkB system. Although the precise mechanisms vary, all of these agents work by inhibiting NFkB activation, thus preventing the expression of genes involved in inflammation and cancer development. Here we summarize familiar nutrients whose NFkB-related actions are now coming to light.

Antioxidants

Antioxidants are known to reduce inflammation and cancer risk. The identification of NFkB as the common link to both processes may serve to explain how these substances operate. Vitamins E and C have been shown to reduce inflammatory cytokine production that is a consequence of NFkB activation.20

N-acetylcysteine inhibits NFkB, which is likely the mechanism by which it confers its health-promoting effects.21 S-adenosyl-methionine (SAMe) exerts some of its powerful anti-inflammatory effects by reducing NFkB activation.22 The potent antioxidant lipoic acid binds to and inhibits NFkB in the cell’s nucleus.23 Zinc may also exert its antioxidant effect by reducing NFkB activation.24

Essential Fatty Acids and Other Lipids

The omega-3 fatty acids are also known to reduce inflammation and decrease the production of inflammatory cytokines. Evidence is emerging that these effects occur due to inhibition of NFkB activity by eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other essential fatty acids in this class.25-27

EPA and DHA protect the eye’s retinal cells from oxidative damage. Moreover, these fatty acids may impair the overgrowth of blood vessel cells that occurs in several retinal diseases, by reducing the production of inflammatory cytokines, vascular growth factors, and adhesion molecules, all via the common pathway of NFkB inhibition.28

Isoflavones and Phytoestrogens

Soy isoflavones and other plant flavonoids are well-established modulators of the immune system’s inflammatory responses. These phytoestrogens (plant-derived, estrogen-like molecules) are known to help reduce the risk of certain hormone-dependent cancers, as well as the risk and severity of osteoporosis.29 Researchers have shown that the isoflavone-induced inhibition of NFkB is the mechanism by which isoflavones reduce the invasiveness of breast cancer and increase programmed cell death in various human cancer cell lines.30-32 Evidence also indicates that isoflavones may act by the same mechanism to inhibit bone loss in osteoporosis.33

Some researchers have speculated that one of the reasons women live longer than men is related to the favorable effects of estrogen on up-regulating antioxidant genes often suppressed by NFkB, suggesting that the phytoestrogens might have similar effects in promoting longevity.34

From Garden to Medicine Chest

Herbs and spices from around the world have long been sought for their pleasing flavors and healing qualities. Even today, these plant extracts are valued worldwide for promoting health and fighting disease. Scientists are discovering that many of these natural agents act through the universal mechanism of inhibiting the over-expression of NFkB.

Curcumin is a compound found in a number of South Asian spices, most prominently in turmeric, a component of curry seasoning.

Curcumin has well-established antioxidant and anti-inflammatory effects.35,36 The extent to which curcumin exerts these effects by inhibiting NFkB is becoming increasingly clear.37 Curcumin acts directly within the cell’s nucleus and also acts on substances that activate NFkB. For example, it binds iron and copper in brain tissue, reducing the activation of NFkB that is associated with the production of amyloid beta proteins in Alzheimer’s disease.35

Strong evidence suggests that curcumin may fight the following inflammatory diseases:
  • Colitis. Dietary curcumin supplements strongly suppressed NFkB activation in a rat model of colitis,38 resulting in both decreased tissue wasting and colonic inflammation. When curcumin was given to experimental animals before the induction of colitis, there was reduced NFkB activation and less visible damage to the colon.39 This effect was accompanied by reduced activity of several enzymes involved in inflammation in the gut.

  • Liver disease. The development of alcoholic liver disease, resulting in chemical hepatitis and eventually cirrhosis, has recently been associated with NFkB-mediated gene expression. When laboratory rats were fed sufficient alcohol to produce alcoholic fatty liver with liver cell inflammation and necrosis, dietary curcumin inhibited NFkB activation, preventing both the microscopic and biochemical changes associated with alcoholic liver disease.40 In an experimental model of non-alcoholic fatty liver degeneration (which induces substantial oxidative stress), investigators found that dietary curcumin significantly reduced inflammation and the release of inflammatory modulators through NFkB inhibition.41

  • Chronic neurodegenerative diseases. NFkB-induced inflammation involving brain glial cells is thought to be one mechanism contributing to the formation of amyloid beta proteins, which are characteristic of Alzheimer’s and other degenerative brain diseases.42 In several recent studies, curcumin has been shown to reduce the glial cell expression of inflammatory mediators.43,44 Curcumin likewise has been shown to reduce amyloid beta formation in animal models by inhibiting NFkB.45,46

  • Arthritis. Curcumin’s inhibition of NFkB reduces the degenerative changes to arthritic joints.47,48 Just this year, curcumin was shown to enhance the anti-inflammatory effects of the COX-2 inhibitor drug celecoxib.49 This is an important finding, since COX-2 inhibitors have adverse effects on the cardiovascular system. This caused scientists to propose that co-treatment with curcumin could reduce the dose of selective COX-2 inhibitors required to achieve significant relief from inflammation.

  • Cancer. Curcumin has been found to suppress, retard, and even reverse cancer development at each stage of the disease.50 By inhibiting NFkB, curcumin reduced expression of proteins needed by cancer cells for proliferation (the promotion stage) and for invasion and metastasis (the progression stage).51 Curcumin also reduces cancer progression by increasing cell death in cancer cells, thereby depriving them of the “immortality” they need to survive and invade other tissues.52,53 This has allowed curcumin to be effective in highly chemotherapy-resistant cancers;54 it has also been shown to increase the effect of chemotherapy in animal models of advanced human cancer.51

CURCUMIN: POTENT CANCER FIGHTER
Curcumin has been specifically evaluated against the following human cancer types:

Skin cancer. Curcumin has been hailed as one of the most promising agents in preventing “photocarcinogenesis,” or cancer caused by ultraviolet light.55 Researchers have found that by inhibiting NFkB, curcumin dramatically increases the rate of cell death in human melanoma cells in culture.56 The effect was both dose- and time-dependent, meaning that more curcumin exposure over a longer time increased the rate of cancer cell destruction. Virtually identical effects have been demonstrated in malignant squamous cell carcinoma of the head and neck.57

Prostate cancer. Curcumin inhibits NFkB and sensitizes human prostate cancer cells to the lethal effects of tumor necrosis factor, which speeds up cell death58 and reduces the ability of cancer cells to proliferate.59 In a 2006 study, curcumin was also shown to decrease the invasiveness of prostate cancer cells, by reducing their production of certain protein-digesting enzymes that help the cancerous cells force their way between healthy cells in order to spread. This resulted in significantly fewer metastatic nodules in the experimental animals fed curcumin than in the controls.60

Breast cancer. Primary breast cancers are treated using surgery, radiation, estrogen modulators, and chemotherapy. Curcumin functions via additional anti-cancer mechanisms. Through its effects on NFkB, curcumin enhances the programmed death of cells from human breast cancers61 and their lung metastases.51 In a 2005 study, curcumin also reduced cancer cells’ production of vascular growth factors, adhesion molecules, and other proteins required for sustaining the cells.51 This study also demonstrated that dietary administration of curcumin to laboratory animals decreased the incidence of cancer metastasis to the lung. These results have staggering implications for human use of curcumin as an adjunctive breast cancer treatment.

Cervical cancer. One of the best-known examples of virally induced human cancer is cervical cancer, which is often caused by infection with human papillomavirus. In 2006, curcumin was shown to inhibit the expression of viral cancer genes (initiation), while also down-regulating inflammatory mediators that cervical cells produce under the influence of NFkB during cancer promotion.62

Colon cancer. Although colon cancer is a major cause of death in Western countries, many scientists believe that dietary modification could reduce its impact by as much as 90%.63 Animals with colorectal cancer showed a reduction in their tumor burden when fed curcumin.64 Human colon cancer cells in culture are inhibited by curcumin,65 and their death is markedly enhanced by curcumin.66 Both effects appear to be mediated by NFkB inhibition and related effects on tumor survival genes. Curcumin was also recently found to markedly enhance the anti-tumor effectiveness of the COX-2 inhibitor drug celecoxib.67

Lung cancer. Curcumin down-regulates NFkB activation caused by cigarette smoke in human lung cells68 and reduces the expression of genes required for tumor promotion and progression of human non-small cell lung cancers.69 Curcumin also induces cell death in multiple human lung cancer cell lines.70

Blood malignancies. Leukemia and multiple myeloma, two cancers of the immune system cells in the blood, are known to be highly dependent on NFkB activity,71 which makes them natural targets for curcumin treatment. Multiple myeloma cells treated with curcumin showed down-regulation of several gene products required for proliferation, and demonstrated arrested growth and increased cell death.71 In one type of human leukemia cell, curcumin inhibited expression of a variety of NFkB-dependent genes needed for both tumor initiation and progression.72 In adult T-cell leukemia, curcumin prevented the growth of virus-infected cells, but not of normal blood immune system cells.73 Curcumin also stopped cell replication and induced cell death by inhibiting NFkB. These results are promising as a means of suppressing this currently incurable form of leukemia.

Human studies are rapidly catching up with these exciting laboratory findings about curcumin. Phase I (safety and tolerability) trials among patients with high-risk cancers or pre-cancerous conditions have demonstrated that curcumin is absorbed after oral dosing and that humans can tolerate up to 8000 mg per day for up to four months without toxicity.74,75 The scientists who authored these studies have recommended further phase II studies of curcumin for the prevention or treatment of various cancers.



Licorice root extracts are among the oldest remedies in Chinese medicine, and have long been used for their anti-inflammatory, anti-viral, anti-ulcer, and cancer-preventive properties.76,77 More recently, scientists discovered that a major component of licorice inhibited NFkB and protected rat liver cells from alcohol toxicity.78 Another licorice extract inhibited NFkB activation and decreased production of a pro-inflammatory cytokine in human colon cells that had been exposed to an inflammatory challenge.79 These results elegantly demonstrate how NFkB inhibition can interrupt the inflammatory cycle by which cytokines stimulate the production of still more cytokines. Glabridin, another licorice root extract, produces similar anti-inflammatory effects by inhibiting NFkB.80

Capsaicin, the main ingredient in red pepper, has both anti-inflammatory and anti-cancer effects.81-83 Red pepper compounds have long been used to manage inflammatory joint conditions.37 Capsaicin inhibits the induction of two inflammation-provoking enzymes in stimulated macrophage immune cells.82 This effect is attributable to its inhibition of NFkB activation.83 Capsaicin also induces cell death in many cancers by modulating NFkB.81 Like curcumin, capsaicin inhibits the growth of adult T-cell leukemia cells by impairing NFkB activation.84 Capsaicin further impairs cancer progression by reducing levels of vascular endothelial growth factor, thus depriving growing cancers of nutrients.85

Clove extract (eugenol) inhibits NFkB-mediated expression of inflammatory cytokines.86,87 Like capsaicin, eugenol inhibits NFkB activation in stimulated macro-phage immune cells,87 reducing their synthesis of COX-2 and inflammatory cytokines.86 Oil of cloves has been used in dental care for centuries, and eugenol is now widely used to promote healing and prevent excessive inflammation after root canal surgery.88,89

Ginger extracts exert anti-inflammatory activity and stimulate cancer cell death by inhibiting NFkB.90-92 Ginger reduces expression of the key inflammatory enzymes COX-1 and COX-2.93 Topical application of ginger extract inhibits skin inflammation in a mouse model92 by inhibiting NFkB.91 A ginger extract was shown to enhance tumor cell death and down-regulate production of tumor invasion factors by preventing activation of NFkB.90

Basil and rosemary extracts, which contain ursolic acid, reduce cancer cell proliferation and tumor progression through NFkB inhibition.94-96 By inactivating NFkB, ursolic acid prevents initiated cells from reproducing and also triggers tumor cell death.95 This compound further down-regulates molecules that are required for tumor invasion and metastasis.96 Ursolic acid works through its effects on NFkB to induce resting macrophage immune cells, and thus to participate in tumor cell destruction in the early stages of cancer.97 Ursolic acid derivatives that inhibit NFkB have been shown to suppress pro-inflammatory enzyme expression in mouse models of inflammation.98 This effect has been associated with reduced cardiac fibrosis (scar tissue) in the heart tissue of diabetic mice.94

Garlic has now been shown to exert its anti-inflammatory and immunomodulatory effects by inhibiting NFkB.37,99 Garlic extracts lowered NFkB activity by up to 41% in human blood and kidney cells that had been exposed to an inflammation-provoking challenge, thus reducing the expression of certain cytokines.100 These effects may be linked to the observation that a garlic compound inhibits damage to endothelial cells lining blood vessels and reduces atherosclerotic changes.101 Garlic’s inhibition of NFkB leads to reduced production of chemicals that cause lipid peroxidation, and this could provide further protection from atherosclerosis.102 NFkB inhibition is credited for garlic’s ability to protect liver cells from auto-immune damage in an animal model,103 as well as induce cell death in leukemia.104

Pomegranate fruit extract protects cells against the effects of ultraviolet B radiation by inhibiting ultraviolet light-stimulated NFkB activation.105 Pomegranate fruit extract also prevented chemically induced skin cancers in mice through NFkB-mediated effects on both cancer initiation and promotion.106 Blockade of NFkB by pomegranate fruit extract has shown promise in osteoarthritis by inhibiting the production of protein-digesting enzymes and inflammatory cytokines.107 Pomegranate wine reduced the activation of NFkB in vascular endothelial cells by inflammatory mediators or biomechanical stresses,108 thus protecting against atherosclerosis.109

Summary

Scientists have discovered that by controlling our DNA, nuclear factor-kappa beta (NFkB) plays a central role in determining our health and longevity. By integrating signals of inflammation, NFkB appears to be the common link between such diverse conditions as heart disease, cancer, and arthritis.

Agents that control NFkB’s influence within the human body—such as omega-3 fatty acids, phytoestrogens, curcumin, garlic, licorice, ginger, rosemary, and pomegranate—hold great promise in fighting many diverse diseases and in promoting long and healthy lives.

Julius G. Goepp, MD, is a pediatrician with additional certification in pediatric emergency medicine. He received his MD from the University of Maryland and is currently Senior Consultant at Lupine Creative Consulting, Inc., in Rochester, NY.

NFkB-Mediated Diseases:

The activation of NFkB has been linked with a wide variety of diseases in humans. Below is a partial list of disorders that scientists have linked with NFkB:

  • Aging
  • Headaches
  • Pain
  • Cardiac hypertrophy
  • Type I diabetes
  • Type II diabetes
  • Elevated cholesterol
  • Atherosclerosis
  • Heart disease
  • Chronic heart failure
  • Angina pectoris
  • Cancer
  • Alzheimer’s disease
  • Pulmonary disease
  • Kidney disease
  • Gut diseases
  • Skin diseases
  • Sleep apnea
  • Asthma
  • Arthritis
  • Crohn’s disease
  • Ocular allergy
  • Appendicitis
  • Pancreatitis
  • Periodontitis
  • Sepsis.

Source: Ahn KS, Aggarwal BB. Transcription Factor NF-{kappa}B: A Sensor for Smoke and Stress Signals. Ann N Y Acad Sci. 2005 Nov;1056:218-33.



References . . .


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