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Life Extension Magazine

LE Magazine July 2006
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What Is Nuclear Factor-Kappa Beta?

By Julius G. Goepp, MD

How Inhibiting NFkB Helps Fight Cancer

Recent discoveries about NFkB confirm the deadly link between inflammation and cancer. It is well known that nutrients and drugs that reduce inflammation also help fight cancer.8,9 Some anti-inflammatory drugs, however, carry cardiovascular risk.10,11 Scientists hope that therapies that block NFkB may provide safe, effective action against both inflammation and cancer.

The ubiquitous presence of NFkB throughout the inflammation-cancer cycle suggests that the next breakthroughs in cancer treatment will likely center on the inhibition of NFkB and its actions. As scientists learn more about NFkB and the complex systems that regulate it, they also learn more about the wide array of substances that can inhibit its dangerous actions. For example, the anti-inflammatory drug ibuprofen inhibits not only the COX-2 enzyme but also NFkB,12 and has a well-established safety record. This drug, as well as many natural inhibitors of NFkB, will therefore play an important role in controlling the inflammatory components of tumor formation and growth.

Because the NFkB factors are active in both the cancerous cells and inflammatory cells in tumors, nutrients or drugs that can inhibit NFkB show tremendous promise as anti-cancer or cancer-preventive agents.8 Scientists believe that the combination of NFkB inhibition with drugs or cytokines that induce cancer cell death has great promise in fighting cancer.13

Because the NFkB system is also involved in producing healthy immune responses, there are concerns about its long-term inhibition. While NFkB seems to be most profoundly involved in cancer at the stages of promotion and progression,8,14 it may be possible to use inhibitors for relatively short periods. Another potential use for such inhibitors would be in combination with chemotherapy or radiation treatments, as a means of controlling the associated inflammation and enhancing the effects of those treatments.8

NFkB: LINKING INFLAMMATION AND CANCER

NFkB and Cancer Promotion

The impact of NFkB on inflammation and cancer is most prominent in the second stage of cancer development, in which cells with newly mutated DNA are promoted into “immortalized” cancer cells.8 Scientists have identified two general mechanisms by which NFkB acts to promote tumors.

In tissue cells that have become initiated because of DNA damage from toxins, radiation, or free radical attack, activated NFkB “switches on” genes that reduce apoptosis (programmed cell death). These “immortalized” cells can now reproduce in the unregulated fashion characteristic of cancer; that is, they have been promoted.15-17

On the other hand, NFkB activation in inflammatory cells results in increased production of cytokines and other growth factors that support the growth, replication, and invasion of the transformed cancerous cells.8,18.19 Such activated inflammatory cells also provide growing cancers with factors essential to new blood vessel formation, producing a life-sustaining environment for the deranged cancer tissue and further promoting its growth.8

Scientists now think of NFkB as the agent that links the processes of toxic damage and inflammation during the promotion phase of cancer development. Because of NFkB’s actions on DNA-damaged cancer cells, these cells are able to outlive their normal counterparts and multiply. Through its action on healthy (non-cancerous) inflammatory cells, NFkB creates an environment that favors cancerous tissue over healthy tissue, providing yet another “advantage” for the growing cancer.

NFkB and Tumor Progression

Inflammation is linked to cancer not only through tumor promotion, but also through supporting the similarly complex mechanisms of tumor progression.8 Once cancer cells have been promoted, NFkB stimulates production of inflammatory signals that support the cancer’s spread to other tissues, both locally (a process known as invasion) and at a distance (known as metastasis).8

Practically since the science of human cancer biology began, scientists have known that at the core of most solid tumors is a mass of dead, or necrotic, tissue. It is now clear that this necrotic tissue contributes to aggressive tumor growth, and once again, the connection is NFkB.8 Dying tumor cells rupture and release inflammatory mediators, leading to the activation of NFkB, which then “turns on” genes involved in rapid tumor growth and invasion. Once kindled by a small amount of necrosis, a tumor can roar to life like a forest fire from a smoldering ember. NFkB is the strong wind that fans the cancer’s destructive growth.

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.

Turmeric (Curcuma longa)

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

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