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NFκB — Nuclear Factor Kappa B

Date: August 6, 2003

by Chaya Venkat

Role in Immune Response and Cancer

spiral red

A Little Background Science

NF-kappaB (NF-κB) is actually a family of structurally-related proteins that are involved in the control of a large number of normal cellular and body functions, such as immune and inflammatory responses, developmental processes, cellular growth and apoptosis. In addition, these factors are persistently active in a number of diseases, including cancer, arthritis, chronic inflammation, asthma, neurodegenerative diseases, and heart disease. That makes understanding this process in CLL important — both the cancer and the immune system's response are strongly affected by the triggering of NF-κB. Additionally, therapeutically targeting the NFkB pathway offers a potential method of reducing inflammation and reducing tumor growth rate.

The NF-κB Pathway

The NF-κB pathway and the manner in which it interacts with cellular mechanisms is one heck of a complex area, and much jargon to get through before one can pick up little nuggets of information. Here are a couple of articles that can get you started if you are inclined to do some reading.

Article in Clinical Chemistry

Article in the Journal of Clinical Investigation.

Basically, NF-κB is a complex of very potent proteins that is kept in an inactive state in the cytoplasm (the portion of the cell outside the nucleus) under normal conditions. When the cell is stimulated in some way that makes it necessary for the cell to protect itself from DNA damage (such as UV radiation, heat, attack by toxic chemicals, etc.), this is the defense mechanism of the cell that kicks into action. The NF-κB is broken free of its inhibitory tether on the cytoplasm, migrates into the nucleus of the cell, where it triggers up-regulation of anti- apoptosis genes, and down-regulation of pro-apoptosis genes. In other words, the cell becomes a lot harder to kill and refuses to hear signals to commit suicide. Activated NF-κB fragments also trigger cell differentiation, so that the cell goes from a resting state to a proliferating state, making more copies of itself. All of which is necessary under normal conditions, when the cell is trying to survive an attack and trying to make more copies of itself to go on the offensive against whatever virus, dangerous chemical and the like is attacking it. 

The bottom line is this: NF-κB is normally inactive in resting cells. When it is activated, it can cause the cells to develop survival advantage, resist cell death — and resist chemotherapy drugs. Many types of cancer cells, including CLL cells, are shown to have very high levels of activated NF-κB, supporting this view of its importance in promoting malignancy.

The problem is that leukemia and lymphoma are cancers of the very immune system that is supposed to protect the body. Activation of NF-κB is disproportionately high in cancer cells and a large majority of them are locked into an activated state without any real need to be in such a state. In fact, the vast majority of CLL cells have an activated NF-κB pathway. This gives them survival advantages (down regulated pro-apoptosis genes and up-regulated anti-apoptosis genes) and as a result of NF-κB activation, they also tend to get kicked into a higher rate of proliferation. Particularly interesting is that activation of NF-κB makes the cells less susceptible to "dangerous" chemicals, in this case chemotherapy agents that we want them to react to! 

If I had my way, here are some practical questions to ask the experts: 

  1. Since simple, easily available drugs such as aspirin, Sulindac and other NSAIDs are known to inhibit the activation of NF-κB pathway, barring contra-indications such as low platelet counts and stomach ulcers, should we be taking maintenance regimes of these drugs to slow down the growth of the cancer cells and make them more prone to apoptosis?
  2. Should these drugs be administered concurrently with more standard chemotherapy drugs to increase the potency of the latter? Is this why glucocorticoids, such as Dexamethasone and prednisone, anti- inflammatory drug that stop NF-κB pathway from activating, have such a dramatic effect when they are co-administered with other  chemotherapy drugs or monoclonals such as Rituxan? 
  3. Does systemic inhibition of NF-κB pathways put the patient at risk of the infections, since the body is handicapped in not being able to fight legitimate invaders that does require an inflammatory response, and which needs the activation of the NF-κB pathway? 
  4. Are anti-viral medications more effective in combination with NF-κB inhibitors, especially in the case of DNA viruses such as EBV, HSV, HCV and HPV, since blocking the NF-κB pathway inhibits cell proliferation, something that these replicating viruses need? 
  5. The blocking of the NF-κB pathway can be done at a number of points, by different drugs. For example, NSAIDs and glucocorticoidal drugs attack this pathway at different points. Does a multi-pronged  approach have a better chance of shutting down this pathway?
  6. Does a maintenance therapy of NSAIDs and nutritional supplements to effectively shut down NF-κB pathway, in combination with low-dose metronomic administration of chemotherapy drugs present a relatively non-toxic method of maintaining long term control over cancer and its secondary effects? 

I could think up a dozen more questions if I sat down to it, but this would be a good start.

NF-κB As Therapy Target

OK. Now for the interesting stuff. Below are a couple of abstracts that will gladden the hearts of those who swear by the beneficial effects of nutritional supplements. The first of the abstracts cited below comes from M. D. Anderson. I will try to describe how it validates some of the food based phytochemicals we have discussed before (see Chemoprevention). 

Unfortunately the abstract from Bharti and Aggarwal below does not list the agents that block activation of NF-κB, and thereby provide some protection from the initiation and/or progression of cancer. The full article does, and I thought I would share some of the items on that list with you guys, save you the $30 purchase price of the article. Here are some of the more well known food based supplements that are effective in blocking the activation of NF-κB: 

Curcumin (extract from the yellow spice turmeric)
Green tea extracts
Vitamins A and E
Resveratrol (found in red wine)
Fish liver oils
Celebrex and aspirin
Sulforaphane (found in cruciform vegetables such as broccoli)

There are others on the list, I am just listing some of the better known ones that we have discussed before on CLL Topics. 

We are all aware CLL is an indolent disease, it does not progress as fast as some of the other cancers. This is because the rate at which new cancer cells are added is only slightly higher than the rate at which they die. If the disease were more aggressive, the rate of birth would be much higher than the rate of death. Now imagine what will happen if you are able to decrease, even slightly, the rate of birth of new CLL cells, or to look at the other side of the coin, you are able to increase the rate at which CLL cells already present are induced to commit suicide. Either of these would decrease the overall rate of accumulation of the cancer cells. Because we are talking about an indolent disease, small changes can pay off big time in controlling the progression of the disease. By all means, I would recommend incorporating some of these food elements into your diet. There is also good epidemiological evidence to support their incorporation into a healthy diet. Many of them are widely used in ethnic foods that seems to reduce incidence of cancer in those regions of the world. 

What makes the whole topic even more interesting is that we seem to be on the verge of discovering much more potent compounds that will be effective in blocking NF-κB activation, compounds that have little or no toxicity of any kind. The day may not be too far away when majority of newly diagnosed patients with early stage disease and few health complications are put on daily maintenance dose of a non-toxic compound that effectively keeps their CLL cell population virtually unchanged over the remainder of their natural life. Not a "cure" for CLL, but not a bad deal if you do not have to do anything more onerous than pop a pill a day to keep it under control? Sounds good to me. I expect to focus more on this in the months ahead. 


Nuclear factor-kappa B and cancer: its role in prevention and therapy.

Bharti AC, Aggarwal BB.

Cytokine Research Section, Department of Bioimmunotherapy, M. D. Anderson Cancer Center, University of Texas, Box 143, 1515 Holcomb Boulevard, Houston, TX 77030

Cancer is a hyperproliferative disorder in which invasion and angiogenesis lead to tumor metastasis. Several genes that mediate tumorigenesis and metastasis are regulated by a nuclear transcription factor, nuclear factor kappa B (NF-kappaB). A heterotrimeric complex consisting of p50, p65, and IkappaBalpha, NF-kappaB is present in its inactive state in the cytoplasm. When NF-kappaB is activated, IkappaBalpha is degraded and p50-p65 heterodimer is translocated to the nucleus, binds the DNA (at the promoter region), and activates gene. Research within the last few years has revealed that NF-kappaB is activated by carcinogens, tumor promoters, inflammatory cytokines, and by chemotherapeutic agents. The activation of NF-kappaB can suppress apoptosis, thus promoting chemoresistance and tumorigenesis. Interestingly, however, most chemopreventive agents appear to suppress the activation of the NF-kappaB through inhibition of NF- kappaB signaling pathway. These chemopreventive agents also sensitize the tumors to chemotherapeutic agents through abrogation of NF-kappaB activation. Overall, these observations suggest that NF-kappaB is an ideal target for  chemoprevention and chemosensitization. This article reviews evidence supporting this hypothesis.

Biochem Pharmacol 2002 Sep;64(5-6):883-8 

PMID: 12213582

Surg Oncol 1999 Nov;8(3):143-53 

The role of NF-kappaB/IkappaB proteins in cancer: implications for novel treatment strategies.

Schwartz SA, Hernandez A, Mark Evers B. 

Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555

The nuclear factor-kappaB (NF-kappaB) family of transcription factors are involved in multiple cellular processes, including cytokine gene expression, cellular adhesion, cell cycle activation, apoptosis and oncogenesis. Constitutive activation of NF-kappaB has been described in a number of solid tumors and this activation appears to affect cancer cell survival. Inhibition of NF-kappaB has been shown to enhance the sensitivity of some cancer cell lines to antineoplastic- or radiation-induced apoptosis. Furthermore, suppression of NF-kappaB results in attenuation of cancer cachexia in a mouse tumor model. Studies are underway to further delineate the role of NF-kappaB in cancer cell survival, growth and resistance to standard chemotherapy and radiation regimens. Moreover, the effects of novel therapeutic agents which specifically target NF-kappaB proteins are currently being assessed in experimental models of cancer cell growth both in vitro and in vivo. In this review, we discuss the possible involvement of NF-kappaB in the growth of various solid tumors and potential future treatment strategies based on NF-kappaB inhibition. 

PMID: 11113665

An Authoritative Reference

Here is a link to the website to end all websites on the subject of NF-κB. For those of you who have become intrigued by this area of research ( I am most certainly one of the intrigued folks), this site has excellent information. It is funded in part by the Lymphoma and Leukemia society, so some of your dollar donations went to work here. Do browse, if you have a little time: 

This link may also be accessed at If the links provided here prove inaccessible, you may want to conduct a Google search on Dr. Thomas D. Gilmore Biology Department, Boston University. This resource appears to suffer from server variability but it is worth seeking out.

NSAIDS to Inhibit NF-κB?

Speaking hypothetically, would you like to have a small, cheap, totally non-toxic pill that you pop once a day, and know that it will keep your CLL from progressing for a long, long time? Not a cure mind you, but the next best thing? If newly diagnosed and early stage patients can stay that way indefinitely, and patients who have been through frontline therapies that got us a good remission can maintain that remission for years and years, what is not to like about that? Read on, some interesting new developments suggest this is not such a pipe dream, clinical trials based on this concept are likely to start in the next couple of months. 

But, as always, I need to walk you through some of the background science before we can get to the main point. A couple of readers wrote and complained that I force people to wade through all this science stuff. Why can't I just give the punch line in a nice sound bite? Guilty as charged. I belong to the old school where learning is considered an active process, and real learning does not happen in passive spoon-feeding of sound bites. Fortunately for long winded people like me, visitors to this website are anything but a captive audience: your visits are voluntary and there is little doubt of the sincerity of your motivation! Much of the science below has been covered in detail in previous articles, it may be well worth your while to dig them out and refresh your memory. Some of the keywords you may wish to use in your search are: NSAID, Cox-1, Cox-2, angiogenesis, NF-κB, CD23. 

Background on NSAIDs

We are all familiar with NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), the most common one of the family being good old aspirin. Almost all of us pop a few of these from time to time, to relieve pain and reduce inflammation. 

We have learnt in recent times that a there is a strong relationship between chronic inflammation and cancers of many sorts. Inflammation is one of the body's defenses when it is under attack; for example the site of a bug bite gets inflamed and red, the inflammation is the signal for the body to get the immune system cells activated and rush to the site of the attack, to deal with the foreign proteins injected into your skin by the bug that bit you. But if the inflammation is chronic and continues for a long time, there can be negative consequences. As in the story of the boy who cried "Wolf!" too many times, pretty soon the immune system stops reacting appropriately when the alarm is sounded. The inappropriate response can be either getting lazy and not getting out the troops and killing the enemy; or the reverse of the coin, going berserk and attacking perfectly good cells of the body for no cause. The first is an example of how a confused and lazy ("anergic") immune system lets cancer cells establish a foothold, without killing them on the spot. The second is an example of immune system attacking the body's own cells in various forms of autoimmune diseases, such as AIHA (autoimmune hemolytic anemia), where the red blood cells are attacked and killed by the immune system. This then is the connection between chronic inflammation and cancer, the subversion of the finely tuned machinery of the immune system. 

Study of inflammation and how it influences different systems in the body has therefore become an important aspect of oncology. We have learned a great deal about why NSAIDs like aspirin, Ibuprofen etc are so effective in reducing inflammation and associated pain. In this context, Cox-1 and Cox-2 are two enzymes that have become famous in the popular press. Cox-1 is expressed through out the body, all the time, and it is an important enzyme for protecting things like the lining of your stomach. Cox-2, on the other hand, is expressed under special circumstances only, such as when there is inflammation. This is the basis of the popularity of new drugs like Celebrex and Vioxx, over much cheaper and older drugs like plain aspirin. Aspirin inhibits both Cox-1 and Cox-2 enzymes, and therefore if you are in the habit of popping aspirins all the time (never mind if they are "safety-coated"), you are running a significant risk of stomach ulcers caused by inhibition of the protective effects of Cox-1 on the lining of your stomach. Celebrex and Vioxx are the new generation of NSAIDs, the so-called selective Cox-2 inhibitors. The idea is that by selectively inhibiting only Cox-2 enzyme, they can be used safely over long periods of time for inflammatory conditions such as arthritis, since it is the Cox-2 that is important in controlling inflammation. 

There have been recent reports that the "selective" Cox-2 inhibitors are not so selective after all, that they too mess with the Cox-1 enzyme to some degree and therefore you are not completely protected against stomach ulcers and the like. Both Cox-1 and Cox-2 are enzymes that control a complex cascade of "prostaglandins", and scientists are still trying to figure out all the details. 

Much more specifically, the part of the inflammation process inflammation that interests us as cancer patients is our old friend the NF-κB pathway, which is triggered when the body goes into an  inflammatory mode. The key here is the fact that a cell whose NF-κB pathway has been turned on is a lot harder to kill, and it refuses to hear signals from the rest of the body to commit suicide. 

A number of drugs are known to inhibit the NF-κB pathway. Among them are the NSAIDs like aspirin and Celebrex, chemotherapy drugs like Prednisone and Thalidomide, "neutraceuticals" like curcumin from turmeric, catechols from green tea, resveratrol from red wine etc. The trick is finding a potent and strong NF-κB pathway inhibitor that does not have dangerous side effects. Long term use of NSAIDs can cause stomach ulcers, others such as thalidomide are also anti-angiogenesis drugs that can interfere with wound healing, steroids such as prednisone have many side effects, and neutraceuticals such as curcumin are not easy to get going through out the body, they have poor "bioavailability profile", for most of them it is basically in at the mouth and out at the other end. Now for the punch line: 

If you have read "Through the looking glass", or heck just preened in front of the mirror recently, you are aware that objects and their mirror images are not exactly identical, they are, well, mirror images of each other. The same is true of chemical molecules as well. Sufficiently complex molecules have mirror image versions of themselves that are almost, but not quite identical. The two forms are called "R" and "S" enantiomers. There are "R-Ibuprofen" and "S-Ibuprofen" molecules, for example. The two are identical in every way, except for the fact that they are each other's mirror image. Almost always, the drug you get when you buy Ibuprofen is a mixture of the R and S forms, since it costs too much to separate them out. And since the two forms are so similar, they are expected to behave the same way, so why bother. 

As it turns out, not quite the same behavior. It is found that the "S" form of many NSAID drugs is what is responsible for the Cox inhibition, and control of the prostaglandin cascade processes initiated by these enzymes. The "R" form of the drugs does very little Cox-1 or Cox-2 inhibition. But, and here is the punch line, what the R-NSAIDs do very well is inhibit NF-κB pathway, a whole lot better than the mixture of R + S versions in the original NSAID. Aha! An effective way to control the specific pathway that would otherwise makes tumor cells hard to kill, and allows them to multiply like rabbits! Now we are cooking! 

I would expect that not all R-NSAID drugs are equally good as cancer therapy drugs. In addition to Ibuprofen I mentioned a couple of time above, another NSAID which is getting some attention is "R-Flurbiprofen". It is already in clinical trials for prostate cancer. (Why prostate cancer? Some one told me this is an "easy cancer" to monitor, since all they have to do is a blood test and measure the PSA number, to get a good fix on the state of the cancer. No need for bone marrow biopsies, CAT scans to measure size of lymph nodes, spleen etc. Sigh... Not only did we have to get cancer in the first place, we had to get one that is tough to measure, so we are never the first ones to get a shot at the new developments). PubMed abstracts for both R-Ibuprofen and R-Flurbiprofen are below, suggesting the unique behavior of these particular mirror image molecules in controlling NF-κB activation. Also below are URLs to some useful reference articles, as well as the URL to the website of Myriad Pharmaceuticals, the owner of R-Flurbiprofen. Rumor has it this particular one may make it into CLL clinical trials real soon. 


  1. Here is a terrific article with lots of detail on the connection between chronic inflammation and cancer. The full article is available, free of charge: Chronic Inflammation and Cancer.
  2. And this makes the connection between cancer and the activation of NF-κB pathway
  3. Here is a link to an article in which I summarize the connections between viral drivers, cancer proliferation, NF-κB pathway, etc.: Viral Drivers
  4. Here is the link to the article whose abstract appears below.


FASEB J. 2001 Jan;15(1):2-4. Epub 2000 Nov 14.

Inhibition of NF-kappaB and AP-1 activation by R- and S-flurbiprofen.

Tegeder I, Niederberger E, Israr E, Guhring H, Brune K, Euchenhofer C, Grosch S, Geisslinger G. Zentrum der Pharmakologie, Johann Wolfgang Goethe-Universitat, Frankfurt, 60590 Frankfurt am Main, Germany. 

R-flurbiprofen is considered the 'inactive' isomer of the nonsteroidal anti-inflammatory drug (NSAID), flurbiprofen, because it does not inhibit cyclooxygenase (COX) activity. However, previous studies have revealed that it has antinociceptive and antitum or effects not due to epimerization to the cyclooxygenase-inhibiting S-isomer. Here, we show that R-flurbiprofen has additional anti-inflammatory activity comparable with that of dexamethasone in the zymosan-induced paw inflammation model in rats. Different criteria suggest that the observed effects are mediated at least in part through inhibition of NF-kB activation: R-flurbiprofen inhibited i) LPS-induced NF-kB DNA binding activity in RAW 264.7 macrophages, ii) translocation of the p65 subunit of NF-kB into the nucleus of these cells, and iii) zymosan-induced NF-kB-dependent gene transcription in the inflamed paw and spinal cord of rats. S-flurbiprofen produced similar effects but was less potent. In addition, R-flurbiprofen inhibited DNA binding activity of AP-1, another key regulatory transcription factor in inflammatory processes. Because R-flurbiprofen does not cause gastrointestinal mucosal damage or other side effects associated with long-term NSAID or glucocorticoid use, it might be a useful drug in inflammatory or other diseases in which increased or constitutive NF-kB and AP-1 activation are involved in the pathophysiological processes. 

PMID: 11099482

Br J Pharmacol. 1998 Feb;123(4):645-52. 

Modulation of transcription factor NF-kappaB by enantiomers of the nonsteroidal drug ibuprofen. 

Scheuren N, Bang H, Munster T, Brune K, Pahl A. Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nurnberg, Erlangen, Germany. 

1. The nonsteroidal drug ibuprofen exists as an R(-)- and S(+)-enantiomer. Only the S(+)-enantiomer is an effective cyclo-oxygenase inhibitor, while the R(-)-enantiomer is inactive in this respect. Thus the molecular mechanism by which R(-)-ibuprofen exerts its anti-inflammatory and antinociceptive effects remains unknown. 2. In this study the effects of the enantiomers of ibuprofen on modulation of transcription factors have been examined with electrophoretic mobility-shift assay (EMSA), transient transfection experiments, confocal immunofluorescence and nuclear import experiments, to determine their selectivity and potency as inhibitors of the activation of transcription factor nuclear factor-kappaB (NF-kappaB). 3. R(-)-ibuprofen (IC50: 121.8 microM) as well as the S(+)-enantiomer (IC50: 61.7 microM) inhibited the activation of NF-kappaB in response to T-cell stimulation. The effect of ibuprofen was specific because, at concentrations up to 10 mM, ibuprofen did not affect the heat shock transcription factor (HSF) and the activation of NF-kappaB by prostaglandin E2 (PGE2). Very high concentrations of ibuprofen (20 mM) did not prevent NF-kappaB binding to DNA in vitro. Immunofluorescence and nuclear import experiments indicate that the site of ibuprofen action appeared to be upstream of the dissociation of the NF-kappaB-IkappaB-complex. 4. Our data raise the possibility that R(-)-ibuprofen exerts some of its effects by inhibition of NF-kappaB activation. 

PMID: 9517383

Too Much of a Good Thing: NF-κB Blockade

Our discussion of NFkB inhibition raised a natural question from some of our members. Some have speculated that a high dose combination of every available NF-κB blocker out there may shut down this pathway completely, for all practical purposes, and make sure the CLL has no chance of growing back. Is this indeed a possibility? Can we take this approach to getting closer to that elusive "cure"?? 

My answer, in one word, is: No!! Not on your life, you have to be crazy to do something like that. (O.K, that's more than one word, I am busted). 

I would not recommend "heavy-duty" NF-κB blockade for CLL patients, or anyone for that matter. NF-κB is a necessary and vital pathway in our bodies, and you would be very foolish if you tried to push it too far out of its natural equilibrium, in either direction. 

For example, total suppression of NF-κB in mice studies show that they are not able to mount sufficiently vigorous immune response when subjected to attack by bacterial infections or other pathogens. As we discussed before, NF-κB is the emergency pathway that the body uses to produce fighting troops quickly, when faced with an immune emergency. Mice that have Nf-KB pathway blocked are also more at risk of death from sepsis. 

For example, in addition to controlling the functioning of the immune system, NF-κB activity also regulates the proper functioning of our skin. This is the single biggest barrier between ourselves and the rest of the universe out there, some of it decidedly not friendly to us. Mice whose NF-κB pathway has been genetically altered, so that it is shut down to a very large degree have a much higher incidence of squamous cell carcinoma. Even the "heartbreak of psoriasis" is thought to be caused by insufficient NF-κB activation. 

NF-κB modulates TNF-alpha (tumor necrosis factor alpha) and many other cytokines. Left unchecked, TNF alpha can do serious damage, as we saw in my recent piece on Crohn's disease. Uncontrolled production of TNF-alpha can cause rheumatoid arthritis, and it can also make you understand the real misery of B-symptoms, as discussed in an article on B-Symptoms, addressing night sweats. 

NF-κB activation to some degree is a necessary function in many neural processes, involved in memory, learning and retention. On the other hand, over stimulation of NF-κB is now considered to be one of the root causes of Alzheimer's, and in fact the NF-κB blocker R-Flurbiprofen that I discussed earlier article is now in clinical trials for Alzheimer's Disease. Look up this clinical trial at the Myriad Pharmaceuticals website.

Too much food is bad for you, makes you fat and unhealthy, it can create life threatening cardiac problems, increase the risk of diabetes and cancer. There have been a number of excellent studies indicating that slightly reduced calorie intake, keeping the body on tight rations, can increase our life span significantly. But total "blockade of food" will surely kill you of starvation. Messing with NF-κB pathway is sort of like that. Inhibiting it too much is decidedly not a good thing.

Every system in our body is on a push-pull, feedback control mechanism, not a static set-point. That's just engineer talk (we have our jargon too, even if we wear hard hats and not white coats), all it means is that our body systems are more like a pendulum swinging back and forth, constantly changing position and adjusting, never static in one fixed position. Moreover, there is a lot of very complex inter-connections between the various systems, and multiple redundancies that we are just beginning to learn. 

Scientists are learning that in general, it really does not help to whack the heck out of any one system, because that is just setting us up for a loophole that the body develops, one that is harder to treat later on. The same theme is reflected in the multiple drug resistance piece I did. Start flooding that old basement with water, and pretty soon the householder goes out and gets himself a nice sump pump to pump out the water. Flood the cancer cells with chemotherapy too many times, and the cancer cells will find a way of pumping out the drug, develop resistance to that particular drug and a bunch more besides.  

That is probably why I like immunotherapy approaches like monoclonal antibodies, such as Rituxan. Rituxan therapy uses much of the body's own immune systems to deal with the problem. Sometimes patients are upset that it takes a while for the effects to show up, as much as a couple of months before the full effect of the therapy can be seen, and the kill rate is rarely 100%, even in the peripheral blood. Well, that is also the reason why there is less chance of the CLL developing / transforming into a more refractory cancer, one that no longer responds to this particular drug. Even with Rituxan, my main concern would be development of a CLL clone that has up regulation of complement inhibitory proteins to a degree that makes Rituxan less effective next time around. Necessity is the mother of invention, and this is true for cancer cells as well. It makes sense not to give the body a reason to invent a new mechanism for subverting what you are trying to do.

We are finding out that the subtle detail and complexity of our bodies means we have to use equally subtle and complex therapies to counter cancer. Very few cancers are treated any more with just one chemotherapy drug, but a variety of drugs in a cocktail, in an effort to try and block all the avenues of escape. Just a few years ago, there was a story on the New York Times front page, that a single angiogenesis drug will soon starve all cancers to death, and a cure is just around the corner. We know now that the body has literally dozens of ways of getting around that single puny road block. Dr. Judah Folkman is a pioneer, and my personal hero for this unique and elegant piece of research. But hubris does not last very long in the field of cancer research. 

CLL can not (repeat, can not) be cured by NF-κB inhibition. If you tweak the proliferation rate of CLL cells so that it is just a tad slower than otherwise, and you also tweak the ease with which they commit suicide (apoptosis) to be just a teeny bit higher, net result is that the rate of accumulation of the CLL cells (rate of birth, minus rate of death) will slow down, just a little. That means the ALC (absolute lymphocyte count) will not climb as fast as it would otherwise. 

How much is "just a little"? I am guessing, but I would be happy if the rate at which the CLL grows back is reduced by only a modest 10%. CLL is an indolent disease, which means the cancer cells do not accumulate too fast. So we can expect to see real differences in length of remissions, even with small changes in the rate of its growth. Even if you had the capability to shut down NF-κB pathway completely, 100%, you would not want to do this, and try to cut the rate of accumulation of CLL cells to zero (i.e., "cure" the CLL). If you do, two things can and will most likely happen: (1) the CLL finds some other way to grow, a redundant system that we have not considered, and keep growing, probably even faster than before. (2) you would be dead because some other truly vital system in your body comes to a screeching halt because NF-κB is shut down 100%. CLL may or may not be cured, but the patient is dead. Not a good scenario. 

As in most things in life, moderation is a virtue. In cancer therapy, this is particularly so. One of the reasons why we have discussed curcumin and green tea on this website is that both of these are food based products, with a long history of use in ethnic cuisine. They probably are not as potent as synthetic compounds that would do a better job of blocking Nf-KB — and probably safer because of that very fact. But even with these agents, moderation and patience is the watchword.

Retarding Tumor Growth with NFkB Inhibitors

Can we delay the need for therapy through the judicious (and safe) use of NF-κB inhibitors? This is an excellent question. These are the kinds of issues we should be discussing with our oncologists, to achieve a two-way information flow. 

There is no question in my mind, if we can slow down the rate of progression of the disease, stay in early stages longer, be able to defer therapy for a while more without being foolish about it, that can only be good. I think of it as buying time. There is a real explosion of new research and information coming down the turnpike. There are choices available now that were not there just a couple of years back. If it is possible to defer therapy, by means of keeping the CLL from progressing as fast as it would otherwise, you will give yourself additional time. Time in which you can learn more, have access to better choices, and make better decisions. Hopefully, you will also use the time to get yourself into better shape, that will make a real difference in how you will respond to therapy. 

As I said, I spoke with Dr. Aggarwal on the phone for over an hour. He is very clear that modest and prudent down-regulation of NF-κB pathway has a huge impact on rate of proliferation of all kinds of cancer cells, without harming other systems in the body. He sees this as a "chemoprevention" and "cancer control" techniques, a way of preventing, controlling and slowing down cancers. I have attached a couple more abstracts below, the first one is authored by Dr. Aggarwal. 

As for the choice of specific NF-κB blockers, you would have to do your own reading and come to your own conclusions. My own preference would be to give more weight to toxicity and safety issues, even if the choice is then not as effective as some other material. Food "phytochemicals" have the benefit of being part of normal food consumption patterns, as long as one does not go too far out on a limb on the dosage levels. NSAIDs do a lot more than just suppress NF-κB, and there is also the issue of stomach ulcers. I am waiting to get more information on the R-Flurbiprofen from Myriad, since this is an optical isomer of a commonly used NSAID, but one that has none of the COX effects of normal NSAIDs. It is getting good press in Alzheimer's clinical trials, as well as in prostate cancer.


Biochem Pharmacol. 2002 Sep;64(5-6):883-8.

Nuclear factor-kappa B and cancer: its role in prevention and therapy.

Bharti AC, Aggarwal BB.

Cytokine Research Section, Department of Bioimmunotherapy, M. D. Anderson Cancer Center, University of Texas, Box 143, 1515 Holcomb Boulevard, Houston, TX 77030

Cancer is a hyperproliferative disorder in which invasion and angiogenesis lead to tumor metastasis. Several genes that mediate tumorigenesis and metastasis are regulated by a nuclear transcription factor, nuclear factor kappa B (NF-kappaB). A heterotrimeric complex consisting of p50, p65, and IkappaBalpha, NF-kappaB is present in its inactive state in the cytoplasm. When NF-kappaB is activated, IkappaBalpha is degraded and p50-p65 heterodimer is translocated to the nucleus, binds the DNA (at the promoter region), and activates gene. Research within the last few years has revealed that NF-kappaB is activated by carcinogens, tumor promoters, inflammatory cytokines, and by chemotherapeutic agents. The activation of NF-kappaB can suppress apoptosis, thus promoting chemoresistance and tumorigenesis. Interestingly, however, most chemopreventive agents appear to suppress the activation of the NF-kappaB through inhibition of NF-kappaB signaling pathway. These chemopreventive agents also sensitize the tumors to chemotherapeutic agents through abrogation of NF-kappaB activation. Overall, these observations suggest that NF-kappaB is an ideal target for chemoprevention and chemosensitization. This article reviews evidence supporting this hypothesis. 

PMID: 12213582 

Carcinogenesis. 2000 Oct;21(10):1885-90. 

Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced NF-kappaB activation by tea polyphenols, (-)-epigallocatechin gallate and theaflavins. 

Nomura M, Ma W, Chen N, Bode AM, Dong Z. 

The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912

(-)-Epigallocatechin gallate (EGCG) and theaflavins are believed to be the key active components in tea for the chemoprevention of cancer. However, the molecular mechanisms by which EGCG and theaflavins block carcinogenesis are not clear. In the JB6 mouse epidermal cell line a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), which causes cell transformation at high frequency, markedly induced NF-kappaB activation. We found that EGCG and theaflavins inhibited TPA-induced NF-kappaB activity in a concentration-dependent manner. These polyphenols blocked TPA-induced phosphorylation of IkappaBalpha at Ser32 in the same concentration range. Moreover, the NF-kappaB sequence-specific DNA-binding activity induced by TPA was also inhibited by these polyphenols. These results suggest that inhibition of NF-kappaB activation is also important in accounting for the anti-tumor promotion effects of EGCG and theaflavins. 

PMID 11023547

Review Article

Link to Full Article:

Molecular Interventions. 2:22-35 (2002)

Inhibition of Nuclear Factor Kappa B (NF-B): An Emerging Theme in Anti-Inflammatory Therapies

Fulvio D'Acquisto, PhD, Michael J. May, PhD and Sankar Ghosh, PhD

Section of Immunobiology and Department of Molecular Biophysics and Biochemistry Howard Hughes Medical Institute Yale University School of Medicine New Haven, CT 06510

The application of anti-inflammatory therapies began thousands of years ago with the use of readily available natural resources. It is only recently, however, that the cellular and molecular mechanisms of inflammation have been appreciated sufficiently to design anti-inflammatory strategies with limited side effects. For example, salicylates and glucocorticoids, two widely used anti-inflammatory drug classes, are now known to inhibit the activation of NF-kB, a transcription factor that regulates the inducible expression of a wide range of proinflammatory mediators. New generations of NF-kB–targeting anti-inflammatory agents that are specific, efficacious, and cost-effective may therefore complement or replace current therapies. In this review, we describe various classes of NF-kB inhibitors and discuss important unresolved issues regarding their use.



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Topic: Inflammation

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