How does chronic inflammation cause cancer?

Chronic inflammation promotes cancer through multiple pathways: Inflammatory cytokines (IL-6, TNF-alpha) activate NF-kB transcription factor which upregulates genes promoting cell proliferation and blocking apoptosis; Reactive oxygen species from inflammation damage DNA causing mutations - estimated 15-20% of cancers linked to chronic inflammation; Inflammation promotes angiogenesis (new blood vessel formation) feeding tumor growth; Inflammatory mediators suppress immune surveillance allowing cancer cells to evade detection; COX-2 enzyme overexpression (increased 10-50 fold in many cancers) produces prostaglandins promoting tumor growth and metastasis.

What is NF-kB and why is it called the master inflammation switch?

NF-kB (nuclear factor kappa B) is a transcription factor controlling over 400 genes involved in inflammation, cell survival, and proliferation. It's chronically activated in most cancers and drives tumor progression. When activated, NF-kB: Increases inflammatory cytokines (IL-6, TNF-alpha) by 200-500%; Upregulates COX-2 enzyme 10-50 fold; Promotes cell survival blocking apoptosis; Enhances angiogenesis and metastasis; Suppresses immune response. Inhibiting NF-kB reduces cancer cell proliferation by 40-70% in studies. Natural NF-kB inhibitors include curcumin, resveratrol, EGCG, omega-3s, boswellia.

Can anti-inflammatory supplements prevent cancer?

Evidence suggests anti-inflammatory interventions reduce cancer risk significantly. Population studies show: Curcumin consumption correlates with 40-50% lower rates of common cancers in India; Aspirin use (anti-inflammatory) reduces colorectal cancer by 30-40% and overall cancer mortality by 15-20%; High omega-3 intake reduces breast cancer risk by 25-30%; Green tea EGCG consumption lowers prostate cancer risk by 30-50%. Key anti-inflammatory supplements: Curcumin (500-1,000 mg daily) inhibits NF-kB by 50-70%; Omega-3 EPA/DHA (2-3 grams daily) reduces inflammatory cytokines 20-35%; Boswellia (400-800 mg daily) inhibits 5-LOX reducing leukotrienes; Resveratrol (200-500 mg daily) suppresses COX-2 and NF-kB.

What inflammatory markers predict cancer risk?

Several inflammatory markers correlate with increased cancer risk: CRP (C-reactive protein) >3 mg/L associates with 30-50% higher cancer risk across multiple types; Elevated IL-6 doubles colorectal cancer risk; High TNF-alpha increases lung cancer risk by 60-80%; COX-2 overexpression found in 80-90% of colorectal cancers; NF-kB activation present in most solid tumors. Testing inflammatory markers: hsCRP - widely available, target <1 mg/L optimal; IL-6, TNF-alpha - specialty labs; Omega-3 index - low levels (<4%) indicate higher inflammation and cancer risk. Reducing these markers through diet, supplements, lifestyle may significantly lower cancer incidence.

What dietary changes reduce cancer-promoting inflammation?

Anti-inflammatory diet dramatically reduces cancer risk: Mediterranean diet adherence lowers cancer mortality by 20-30%; High vegetable/fruit intake (8-10 servings daily) reduces cancer risk 30-40% through polyphenols and antioxidants; Omega-3 rich fish (2-3 servings weekly) decreases inflammation 25-35%; Minimize pro-inflammatory foods: refined sugars/carbs increase inflammation 40-60%, processed meats raise colorectal cancer risk 18%, excess omega-6 oils promote inflammatory eicosanoids. Anti-inflammatory foods: turmeric/curry, green tea, cruciferous vegetables (broccoli, cauliflower), berries rich in anthocyanins, extra virgin olive oil, nuts (walnuts, almonds), fatty fish, herbs (rosemary, oregano, ginger).

The Inflammatory Factor Underlying Most Cancers

Q: What dietary changes reduce cancer-promoting inflammation?

Anti-inflammatory diet dramatically reduces cancer risk: Mediterranean diet adherence lowers cancer mortality by 20-30%; High vegetable/fruit intake (8-10 servings daily) reduces cancer risk 30-40% through polyphenols and antioxidants; Omega-3 rich fish (2-3 servings weekly) decreases inflammation 25-35%; Minimize pro-inflammatory foods: refined sugars/carbs increase inflammation 40-60%, processed meats raise colorectal cancer risk 18%, excess omega-6 oils promote inflammatory eicosanoids. Anti-inflammatory foods: turmeric/curry, green tea, cruciferous vegetables (broccoli, cauliflower), berries rich in anthocyanins, extra virgin olive oil, nuts (walnuts, almonds), fatty fish, herbs (rosemary, oregano, ginger).

The Inflammatory Factor Underlying Most Cancers Implicated in the onset of 95% of all cancers is a common but under-recognized molecule most people have never heard of: nuclear factor-kappaB or NF-kB.1-3 Emerging research is validating the danger it poses to maturing individuals.

For example, a landmark study4 published late last year confirmed, for the first time, NF-kB’s central role in the onset of malignant breast cancer.

A team of researchers found that breast cancer cells require a specific inflammatory cascade in order to proliferate and metastasize.

As one of the proteins that activates genes involved in inflammation, NF-kB is the master regulator of this pathologic cancer-causing process.

Fortunately, there exists a broad array of nutrients many Life Extension® members already take that have been shown to neutralize and even reverse the cancer-causing inflammatory cascade mediated by NF-kB.

In this article, a comprehensive survey of NF-kB-inhibiting compounds is detailed. You will learn how NF-kB triggers the growth and development of many kinds of tumors, operating as the master switch for cells “pre-loaded” with cancer-causing genes. You’ll also discover compelling evidence about low-cost interventions that suppress NF-kB, switch off lethal cancer genes, and disrupt the inflammatory cascade cancer cells need in order to spread.

Since its discovery in 1986, NF-kB has been known to be closely associated with development of cancer.5 Today we know that most, if not all cancers have abnormally high levels of active NF-kB, which keeps them in a state of sustained inflammation.6 Conversely, certain so-called oncogenes (abnormal genes that can initiate cancer development) act in part by activating NF-kB.7 Together these facts conspire to produce a steady stream of inflammatory and cancer-promoting cytokines within a growing tumor.8

The production of these cell signaling molecules makes it much more likely that a given cancer-prone cell will go on to form a malignant tumor. It can also mean that a given tumor is much more resistant to radiation and chemotherapy, since NF-kB generally promotes cancer cell survival.9

The NF-kB-Cancer Blockade

The NF-kB-Cancer Blockade NF-kB triggers the cascade of events that link inflammation with cancer development. Once that process has been initiated, NF-kB continues to fan the flames, contributing to cancer cells’ invasiveness, ability to stimulate a fresh blood supply, and ability to spread by metastasis throughout the body.

But our knowledge about the damage done by NF-kB can be turned to good. Almost as soon as it was discovered, forward-thinking researchers recognized that if they could block activation of NF-kB, they might break an essential link in cancer development.

We’ve known for nearly 12 years, for example, that we could reduce inflammation in colon cancer cells by treatment with the spice curcumin, a well-known inhibiter of NF-kB activation.10 Blocking NF-kB activation can also sensitize human prostate cancer cells to apoptosis—the programmed cell death that keeps cancers under control.11 And natural molecules that inhibit NF-kB can limit inflammatory changes in the pancreas caused by alcohol.12

The potential for blocking NF-kB offers hope in the context of the deadly HER-2 breast cancer gene. HER-2 cancers are normally highly treatment-resistant and carry a poor prognosis.6 Blocking NF-kB can make the breast cancer cells more amenable to chemotherapy.8,13

Not surprisingly, Big Pharma is intensely interested in discovering new (and profitable) drugs that block NF-kB.14 But nature has provided us with a substantial number of substances that block or inhibit the pro-inflammatory, pro-cancer effects of renegade NF-kB—and they are readily available, affordable, and safe. Let’s look at a sampling.

Nutrients to Quell NF-kB’s Inflammatory, Pro-Cancer Effects

Nutrients to Quell NF-kB’s Inflammatory, Pro-Cancer Effects By some estimates, anywhere from 67% to 90% of human cancers could be prevented by modifications to lifestyle, specifically to diet.14,15 Suppression of NF-kB by phytochemicals present in fruits, vegetables, and many spices has in fact been said to provide the molecular basis for their ability to prevent cancer.16,17

The following nutraceutical agents can bring us closer to successful chemoprevention through their ability to oppose NF-kB’s pro-inflammatory, pro-cancer effects. Unlike single-targeted drugs, most nutraceuticals are multitargeted. That gives them astonishing efficiency and can augment their effectiveness, especially when acting to interrupt complex signaling pathways like those involved with NF-kB.18

Antioxidants

Oxidative damage to DNA, proteins, and other vital structures is a major factor in the initiation, promotion, and spread of cancers. That makes antioxidants important agents in the fight to prevent cancer.19 But many antioxidants can also block NF-kB, adding a valuable degree of specificity to their effects. They do this via a number of closely related but distinctive mechanisms.14

One important way of blocking NF-kB activity is to prevent it from becoming activated by moving into the cell nucleus. That denies NF-kB access to the pro-inflammatory genes that it regulates, thereby preventing the inflammatory response before it starts. Cells with greater levels of internal antioxidant defenses generally have less NF-kB activation. Increasing those defenses is correlated with reduced NF-kB expression in cell nuclei.20,21

A large number of antioxidants are under review for specific NF-kB-blocking activity. These include vitamins C and E, carotenoids, the so-called thiol antioxidants (glutathione, thioredoxin, and lipoic acid), flavonoids and polyphenols, selenium, zinc, and others.14,19,22,23 The flavonoid luteolin, for example, can sensitize cancer cells to chemotherapy agents by suppressing a variety of cell-survival pathways, including NF-kB.24 And zinc, an essential trace element, inhibits NF-kB indirectly by inducing a separate regulatory protein called A-20.25

Antioxidants Milk thistle extracts enhance prostate cancer cell death through apoptosis by reducing levels of NF-kB in the cell nucleus.26,27 The tomato carotenoid pigment lycopene prevents NF-kB activation in prostate cancer by a different mechanism.28 A form of vitamin E called gamma-tocotrienol downregulates NF-kB in pancreatic tumor cells.29 Even certain coffee components, the antioxidant molecules called diterpenes, suppress NF-kB activation.30 And a host of antioxidant compounds derived from black pepper reduce NF-kB activation.31 Finally, the tomato polyphenol lycopene reduces NF-kB activation in a variety of cancer cell types.28

Clearly, the list of antioxidant nutrients with NF-kB-suppressing effects is growing rapidly. A good general rule for the present is to make certain that you are including an adequate supply of potent, high-quality antioxidants as part of your health regimen. Let’s now turn to some specific nutrients that have additional NF-kB-blocking effects that can optimize your cancer protection.

What You Need to Know: The Inflammatory Factor Underlying Most Cancers

A breakthrough study revealed that inflammation is necessary in order for breast cancer cells to proliferate and metastasize.
The master control complex called nuclear factor-kappaB or NF-kB triggers and regulates this inflammatory cascade, which has been implicated in the onset and development of 95% of all cancers.
NF-kB stimulates genes to produce inflammatory cytokines and other signaling molecules that promote cancer growth and development.
Inhibition of NF-kB is a powerful target for cancer prevention and has been shown to reduce cancer-stimulative events at every level of carcinogenesis (cancer development).
A broad array of natural dietary interventions powerfully inhibits pathologic NF-kB activity, comprising a critical strategy in the fight against cancer.

Curcumin

Curcumin is an extraordinary molecule extracted from the spice we know as turmeric. It is among the most potent of the natural inhibitors of NF-kB, and as such has been intensely studied for its anticancer potential.32

Curcumin is beneficial at all three major stages of carcinogenesis: initiation, progression, and promotion.33 Most of that benefit has been linked to its inhibition of NF-kB and subsequent inhibition of pro-inflammatory signaling.33 NF-kB inhibition is also credited with curcumin’s ability to inhibit cancer cell proliferation, invasion, new blood vessel formation, and metastasis.34 Another major consequence of NF-kB inhibition by curcumin is to allow the natural course of apoptosis to take place in cancer cells, triggering them to die off rather than multiply and spread.35

Curcumin is showing promise in treating or preventing some of mankind’s most common, and most dangerous, malignancies. These include chronic lymphocytic leukemias, lymphomas, pancreatic cancers, bladder cancer, colon cancer, and cancer of the bile ducts.36-44 And curcumin can help to suppress the cancer-provoking inflammation generated by obesity, one of today’s most pressing health problems.45

NF-kB and the Cancer Switch

NF-kB and the Cancer Switch NF-kB is scientifically known as a “transcription factor.”92 It regulates how and when the information in certain human genes becomes translated into new protein molecules.

Key among those genes are those that promote inflammatory responses, many of which also promote cell growth, survival, and transformation into cancer.6,22 In fact, in the early 2000s it became clear that NF-kB was the “missing link” between inflammation and cancer.93 Of course, that’s not its only role.

In healthy people, NF-kB serves a vital function just by remaining inactive. That helps to keep the powerful cellular machinery of inflammation running just at idle. When a threat arises, however, NF-kB becomes activated and goes to work within the nuclei of cells (hence the term “nuclear factor”).7

A cell’s nucleus is where all the genetic information is stored in the form of DNA in our chromosomes. Under normal circumstances, NF-kB “lives” not in the nucleus, but in the cell’s cytoplasm, the main body of the cell.7 When an infection or other foreign invader threatens, NF-kB moves from the cell’s cytoplasm into its nucleus.7 Once inside the nucleus, NF-kB binds to specific portions of the chromosome, where it activates transcription of a gene into its protein product.

Many genes that come under the control of NF-kB are pro-inflammatory genes, that is, their products are inflammatory cytokines such as interleukins, tumor necrosis factor, and others. Once the inflammatory stimulus goes away, NF-kB normally disengages from the chromosome and returns to the cytoplasm, and the inflammatory gene stops producing its cytokines. In other words, under normal circumstances, inflammation dies away when it is no longer beneficial.94

But that’s only under normal circumstances, and cancer is anything but normal.

Garlic Extracts

Garlic, like turmeric, has a lengthy history of use in traditional medical systems. When garlic extracts are allowed to age, they stabilize and retain strong antioxidant powers that indirectly down-regulate NF-kB.46 Individual components from such garlic extracts include diallyl sulfide, diallyl disulfide, and thiacremonone, all of which demonstrate direct NF-kB-inhibitory activities.17,47,48

NF-kB inhibition by garlic extracts is showing promise in preventing growth and spread of many tumor types, including colon cancer, malignant neuroblastoma, and melanoma.47-51 Garlic extracts also powerfully induce cancer cell death by apoptosis.49,51

Ginger

Ginger Ginger is a spice from southern Asia, that has many health-giving specific components.52 Gingerol is the chief of these; it is a phenolic compound with antioxidant, anti-inflammatory, and anti-tumor properties.53 Gingerol suppresses inflammation by blocking the movement of NF-kB into the nucleus, with the resulting down-regulation of such inflammatory cytokines as TNF-alpha, as well as inducible nitric oxide synthase (iNOS).52,53 Another major ginger compound, zerumbone, suppresses NF-kB activation induced by a host of common carcinogens, blocking metastasis and invasion while increasing apoptosis.54

Ginger extracts have been used to reduce the viability of gastric cancer cells, ovarian cancers, cancers of the breast, liver, colon, and lung, as well as UV light-induced skin cancers.55-60

Current NF-kB Research

Current NF-kB Research Here’s what we know in 2011 about the relationship between NF-kB and cancer, courtesy of Dr. Sahdeo Prasad of the Cytokine Research Laboratory at the MD Anderson Cancer Center in Houston:5

NF-kB becomes activated in response to a host of factors that account for as much as 95% of all cancers. These triggers include tobacco, stress, dietary components, obesity, alcohol, infections, radiation, and environmental toxins.1-3

NF-kB activation has been linked with the transformation of normal cells into cancer cells (thus NF-kB can be thought of as promoting cancer development).1,95

NF-kB is active at a higher rate in cancer cells than in healthy cells. A developing cancer also increases the amount of active NF-kB.6,13

NF-kB has been linked to the survival of dangerous cancer stem cells, the early “parent” cells of many cancers that are now known to exist in otherwise normal tissues. Cancer stem cells can “self-renew” more successfully than healthy cells.

NF-kB stimulates production of gene products that keep cancer cells from dying naturally through the process of programmed cell death, or apoptosis.96

NF-kB also increases production of gene products associated with proliferation, the rapid and repeated cell divisions that give cancers their aggressive growth characteristics.97

NF-kB controls expression of gene products linked with invasion, new blood vessel growth (angiogenesis), and metastatic spread of tumors.96,98-100

Many carcinogens activate NF-kB, but most effective cancer-preventing (chemopreventive) compounds suppress NF-kB activation.1,15,101

Prasad notes that these observations highlight just how intertwined NF-kB is with cancer growth and metastasis.5 Others have gone on to point out that, though a powerful nemesis, NF-kB also offers myriad opportunities to intervene powerfully and block cancers in their tracks.8,13 As we continue to clarify the close relationship between chronic inflammation and cancer, more and more such opportunities are becoming evident.93

Green Tea

Green tea extracts are widely known for their benefits in preventing many common chronic diseases. Their chief constituents, the catechin family of polyphenols, are powerful antioxidants that are given credit for most of tea’s beneficial effects.61,62 Catechins act at many different targets.18,63,64 Inhibition of NF-kB by green tea catechins has recently been found to be a major mechanism by which they block each stage of carcinogenesis.63-65

NF-kB inhibition by green tea extracts rich in epigallocatechin gallate (EGCG) has been of particular interest.866 EGCG has been shown to produce apoptosis in experimental prostate cancer, inhibit growth of squamous cell carcinomas of the head and neck, inhibit production and limit invasion of experimentally induced breast cancers, reduce the incidence of carcinogen-induced lung cancers, and sensitize melanoma cells to growth inhibition by other agents.67-71

Isoflavones

Isoflavones and isoflavonoids are molecules found in many plants, particularly the bean family. Plants use them as disease-fighting compounds, and also as stimulants for the symbiotic bacteria that help them use nitrogen to build proteins. Isoflavones from soybeans have many beneficial and protective effects in humans as well. The low rate of hormone-related cancers (e.g., breast and prostate cancers) in Asian countries is partially attributed to the high consumption of soy isoflavones in most traditional Asian diets.72,73

Soy isoflavones like genistein are powerful modulators of NF-kB.73 Genistein acts both by preventing NF-kB’s movement into the nucleus to activate inflammatory genes and also by preventing earlier molecular events that would lead to its activation.74 Genistein promotes cancer cell death by apoptosis as a result of down-regulation of NF-kB.74

Isoflavone blockade of NF-kB effects contributes to prevention and modulation of colon75 and lung cancers.76 Isoflavone treatment also makes certain cancer cells increasingly susceptible to radiation and chemotherapy effects, largely because decreased NF-kB activity impairs the cancer cells’ survival signaling pathways.73,77,78

Omega-3 Fatty Acids

Diets rich in omega-3 fatty acids from fish are associated with reduced risk of several types of cancer and other chronic conditions.79,80 The omega-3s are known to be powerful anti-inflammatory agents through their effects on the important inflammatory enzymes like COX-2 and 5-LOX.81 But recent research is also showing that omega-3s can inhibit NF-kB activation by multiple mechanisms, giving them still more powerful control over the inflammation that can lead to cancers.

Omega-3s are now associated with NF-kB-related reduction in inflammation-mediated growth of pancreatic, breast, prostate, colon, and skin cancer cells.82-90 In the case of pancreatic cancer, the omega-3 EPA preserved the integrity of the natural inhibitor of NF-kB.82 Omega-3s used in combination with conventional chemotherapy act synergistically to kill tumor cells, largely through NF-kB inhibition that promotes apoptosis.89,91

Summary

A breakthrough study published late last year revealed that inflammation is necessary in order for breast cancer cells to proliferate and metastasize. The master control complex called nuclear factor-kappaB or NF-kB triggers and regulates this inflammatory cascade, which has been implicated in the onset and development of 95% of all cancers.

NF-kB stimulates genes to produce inflammatory cytokines and other signaling molecules that promote cancer growth and development. Inhibition of NF-kB is a powerful target for cancer prevention and has been shown to reduce cancer-stimulative events at every level of carcinogenesis (cancer development). A broad array of natural dietary interventions powerfully inhibits pathologic NF-kB activity, comprising a critical strategy in the fight against cancer. Scores of new studies detail the effects of NF-kB inhibition on cancer prevention. The low rates of cancers in countries with high dietary intake of natural NF-kB inhibitors points strongly to the value of such agents as functional foods and as nutraceuticals.

In addition to the many natural products outlined here, there’s now strong evidence that vitamin D, Withania somnifera (ashwagandha), and pomegranate extracts have similar NF-kB-blocking capabilities.102-104

The good news for Life Extension members is that they have been using potent NF-kB-inhibiting nutrients for many decades.

+ References

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