Blood tests, more on cyclopamine and…Cancer Vixen

February 26, 2008 / / 2 Comments

Blood tests. Last night I decided that a silly little fever wasn’t going to stop me from taking these tests. So this morning I got up at the crack of dawn, made sure I had no fever (the little coward vanished overnight, hah!), and set off for the hospital, where I met up with Sherlock. We were tested together and were out by 8 a.m. She had work to do so she headed home, while I went to another part of the hospital to have a breath test…ah, no, not what YOU are thinking, no siree! This test will determine if I am infected with Helicobacter pylori. In case you don’t know what I am babbling about, check out my page on Helicobacter pylori and MGUS. In a nutshell: it’s a bacterium that infects the stomach and can cause us a lot of grief, A LOT!, ranging from peptic ulcers to cancer.

A slight aside. Wikipedia provides a fascinating account about how H. pylori was discovered, or rather, rediscovered in the early 1980s more or less, by two Australian scientists, Warren and Marshall, who were the first to successfully culture it. They believed that most stomach ulcers and gastritis were the result of an infection caused by this bacterium and not by stress or spicy foods as had been previously assumed. To prove their point, Marshall drank a Petri dish of H. pylori and developed gastritis. A man after my own heart! Gutsy! You can read the full story on Wikipedia.

Anyway, this was an interesting test. First, using a plastic straw, I had to blow some air into two vials, enough to steam them up. Then I had to drink something that tasted like very bitter lemonade (urea) and wait for a half hour. I then blew into two different vials. That was it. For details on how the H. pylori breath test works, see http://tinyurl.com/33nvay

I will have all my test results back in about three weeks. Probably a few of my values will be altered due to the cold I have been fighting (successfully, so far!!!), but I am hoping they won’t be TOO off. No worries.

A few words on cyclopamine. Yesterday I wrote to CT, asking the question posed by one of my blog readers (see my recent cyclopamine post) concerning water solubility. CT replied: I took cyclopamine tartarate which Logan labs claims is somewhat water soluble. Mice at UTMS took the regular cyclopamine orally for basal cell CA and it worked, so it must be getting absorbed. I note that is does mix well in water. In any event, my M-marker did go down. I will know more when I retest.

Cancer Vixen. While I was waiting to have my breath re-tested this morning, I began reading a book that Sherlock gave to me (grazie!), titled "Cancer Vixen," by Marisa Acocella Marchetto, a cartoonist for the New Yorker (etc.). At one point I almost laughed out loud. I wonder what the other patients sitting in the waiting room thought of me: a grown woman reading and chuckling over what looks like a…comic book! (Not that I cared one whit, mind you!). Hehe.

Anyway, since you already know (if you have been reading my blog for a while) that I have a wacky sense of humour, you won’t be surprised to read that the part that thus far has amused me the most, and I am only on page 20!, is when she is told that she has an "abnormality" (referring to a breast tumour). Oh yeah, that’s a bit of really hilarious news, ujú ja ja ja ja ja jaaaaaa…ñaca-ñaca (that’s an "evil laugh" in Spanish, no kidding; you can find the most peculiar items in Wikipedia…), but I assure you that the cartoons are quite amusing, IF you have a warped sense of humour, that is!

Well, I haven’t read any cartoons since I was in my teens, so this is fun, even though the subject itself (cancer!) isn’t that much…fun, admittedly! Oh, wait, another funny cartoon is the one depicting "possible cancer cells" in a petri dish, "magnified 3 gazillion times." Marisa makes them look like evil little green buggers sticking out their tongues and giving us the…finger. Good job, Marisa, so far. I will keep reading.

Fabulous news!

February 25, 2008 / / 6 Comments

A MMA and Beating Myeloma list friend sent me a fabulous bit of news yesterday morning via e-mail, as follows:

I was diagnosed with MGUS. Feb.06, m-spike 0.03, went up to 0.07, and then I took control, took all your advice and listened to my body. I worked my way to 5 grams of curcumin among other things. Reduced stress, soaked in 104 degree water twice a day. Last test before Dr’s appointment: 0.02. The day of appointment I had another test, just got it back: "NO monoclonal protein detected by the current electrophoresis study.

HURRAY!!!

I asked her for permission to post her story here. She very kindly (thank you!) consented, also providing me with the details of her protocol.

She takes the following: Andrew Weil’s Daily Multivitamin, Daily Antioxidant, Immune System Builders that include ashwaganda, cordyceps, astragalus, Siberian ginseng – the quantities are prepackaged in an AM and PM dose.

She also takes: Life Extension Super Curcumin with Bioperine 800 mg, 3 pills in the morning and 3 in the afternoon. Lysine: 1000 mg, 1/day. Resvera Wine Complex 500 mg, which contains: grapeseed extract, ellagic acid, & resveratrol, 1/day. Guggul Plex 340 mg, 1/day. Zyflamend softgels by New Chapter, 1/day. Yaeyama Chlorella 400 mg., by Yarrow Formulas, 1/day.

She writes: I am anemic if I am not careful and I take Slow FE- 47.5 mg. slow release iron- doesn’t upset my stomach.

Every morning and afternoon, she soaks in a 104 degree hot tub for 35 to 45 minutes and, she adds, there I do nothing but soak- it was hard to learn.

She adds: “I eat lots of veggies, some fruit and meat 2 or 3 times weekly (salmon, or whatever I’m craving, meatloaf last week, buy organic whenever I can). If I crave an old evil food, I eat it- it’s usually not as satisfying as I remember, and it takes care of the craving, although I recently made a German chocolate cake.

Lots of nuts, focusing on walnuts- make my own chocolate bars by roasting walnuts and pouring Ghirardelli’s chocolate (bought at Trader Joe’s) over top, keep it in my freezer for a quick fix.

No coffee, diet anything, fast food. Use real butter (organic) and olive oil- did notice a difference for the better when I gave up Smart Balance. Try to keep all food real—very little pre-prepared. In spring and summer frequent my local farmer’s market. Juice carrots every other day, and buy Green food juice at Trader Joe’s. Drink tons of water.

I have early retired, and I now do projects that used to take 1 day. I now spread them out over 3 or 4 days. If I’m fatigued, I do nothing.

I’m careful to avoid stress, I have started saying no to volunteer situations.

I’m 58, I have neuropathy from the waist down -large areas of no temperature feeling- reflexes not strong below the waist- My doctors are now saying fibromyalgia just because they don’t know. But if I listen to my body I can do anything I want, just slower with planning- I used to be a construction worker and have worn out my spine.

Hope this helps.

Upon rereading this post, I must admit that the list of things that she takes is quite daunting. I don’t take anything except for curcumin, quercetin, flaxseed oil, black cumin oil and an occasional multivitamin (heavy on the B vitamins). That’s my current intake. My list pales in comparison with hers. Hmmm.

At any rate, she will continue to monitor her blood situation every four months for the next year, then will go to every six months. She believes that getting rid of stress has really helped her, as well as ignoring the reports that we shouldn’t build our immune systems. Well, this approach clearly worked in her case! In her own words: I do believe our society demands multi-tasking, major stress, the need to buy more, have more. I think my efforts at doing nothing helped reset my immune system and yes, I ignored those reports that you don’t want to build your immune system.

Speaking of immune systems. Incredible but true: yesterday I began feeling a bit ill. And it just so happens that tomorrow Sherlock and I are supposed to go to the hospital lab to have our Biocurcumax tests done. But this morning I am having chills and, can you believe it?, a low-grade fever. Needless to say, I am quite annoyed! But not too surprised, since all of my students have been ill, with fevers and colds and terrible coughs…SIGH! Che pazienza che ci vuole…Well, unless I get worse, I will go have my tests done anyway. Oh, bother!

Update on cyclopamine

February 21, 2008 / / 17 Comments

Yesterday a myeloma list member reported his test results after five cycles of cyclopamine. He authorized me to post about it. If you have no clue as to what I am writing about, see my August 2 and 3 2007 posts about cyclopamine, or my permanent page (see my Pages on the right, and look under "Other anti-myeloma/cancer supplements").

Here are some details posted by the cyclopamine-taking list member (from now on, I will refer to him as CT, or cyclopamine-taker) took a water-soluble form of cyclopamine for a year and a half. More specifically, he took 200 mg of cyclopamine a day for 14-15 days at a time, every 2-4 months. His m-spike went from 1.0 (achieved after two stem cell transplants two and a half years ago) to 0.2, then to 0.1, and he is convinced that these decreases, the first since his transplants, were due to his cyclopamine intake. Coincidental? Possibly. He reported, by the way, no side effects. Indeed, he feels great.

Okay, but we should not get TOO excited about this substance. The main reason, at least as far as I am concerned, is that it costs an arm and a leg. I had the brilliant idea of seeing if I could order some and ask my parents bring it over to me when they fly to Italy for their regular summer visit, but when I saw what it cost, i.e. thousands of dollars, my eyes almost popped out of my head. No way I could afford it. CT has a cheaper source than what I found online, but it’s still way beyond my budget.

Another list member pointed out that he would be anxious about potential side effects that might not manifest themselves immediately, but perhaps 20 years down the road. But CT (good sense of humour!) said that he would be happy to survive 20 years with myeloma! Indeed. He added that he is well aware that there are possible risks involved in taking a substance that hasn’t been approved by the FDA, but after all, we are dealing with myeloma, not an ingrown toenail (my analogy, actually). So true.

CT reminded us that Dr. Matsui reported in April 2006 at the American Association for Cancer Research (AARC) meeting that cyclopamine caused differentiation of myeloma stem cells. In other words, the myeloma stem cells were eliminated because they did not produce any more cancer stem cells. The stem cells turned into mature plasma cells that eventually died out. Normal cells were not affected, he reported.

For an interesting Science Daily article (2002) on cyclopamine, see: http://tinyurl.com/2zcwut

In PubMed there are 260 studies on cyclopamine. But there is not one clinical trial. Typical.

As usual, I hope this situation will change soon. If it does, I might be first in line!

Update on the update: with this post, I wanted to report on an interesting case, perhaps (I hope!) a crucial one in the battle against myeloma stem cells. I would like to underline, though, that I am not encouraging folks to take cyclopamine. Even though we aren’t pregnant sheep (if you are puzzled about that statement, read my page on cyclopamine: all will be clear ), we still don’t know if there might be harmful side effects (etc.). CT did report that he had none, which is extremely important. In sum, I think this substance should definitely be put on our watch-and-see list. Yes, indeedie!

Another pro-inflammatory cytokine: IL-17

February 5, 2008 / / Leave a comment

About a month ago I read a Science Daily article with an intriguing title: “Protein’s New Role Discovered In Autoimmune Disease.” (see: http://tinyurl.com/yrzaud). In a nutshell, University of Alabama researchers identified a previously unknown effect of a T cell-derived cytokine named interleukin-17, or IL-17 for short. This is an “immunity protein,” that helps induce and mediate pro-inflammatory responses, such as allergies, autoimmune diseases and whatnot. IL-17 also induces the production of many other cytokines, such as the infamous IL-6! Uh-oh!

Now, the news reported in Science Daily is that when the “messenger” signals from IL-17 were blocked, the disease-causing B cells dropped from 17 to 2 percent. Coincidence? Ah, no. As the articles states, “The drop was a clear sign that IL-17 plays a major role on shaping B cells’ ability to create more and more disease-causing antibodies.” So if IL-17 can be inhibited, B cells are slowed down in their efforts to create wacky antibodies. And here I thought B cells were the good guys, the cells that defend us against infections etc. Well, in autoimmune diseases they can go bonkers, as we can read in the Science Daily article.

After reading this article, I immediately checked out if IL-17 is involved in myeloma. Of course it is. Hah, figures! For instance, see the abstract of this 2006 study (http://tinyurl.com/2786gs), which shows that IL-17 “is a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and regulates the production of a variety of proangiogenic factors, such as tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial cell growth factor (VEGF).” Need I add more? Oh, ok, just this bit: the researchers conclude that “IL-17 plays a role in the promotion of angiogenesis and associated disease progression in MM.” Bad, bad IL-17!

I found an interesting bit of information on IL-17 in the MD Anderson October 31^st 2005 “Weekly News and Notes for Patients, Families and Visitors.” The article is titled “New immune cell found to be a key to inflammatory diseases” (see: http://tinyurl.com/2moorw). MD Anderson and other researchers discovered a new type of T-cell, called THi, produced IL-17, which they “linked to an immune system gone awry." An awry immune system? Well, if that doesn’t sound familiar…! Before this discovery, IL-17 was known to play a role in autoimmune and inflammatory diseases, but its origin was a mystery. The study’s lead investigator stated that “These findings suggest that shutting down the activity of these THi cells might stop chronic inflammatory diseases from developing in the first place.” How about that?

Okay, IL-17 is now officially on my list of evil pro-inflammatory cytokines. It is also connected, by the way, to NF-kB (I need to do more research on this topic; I may get to it, someday…). IL-17 also stimulates IL-8, which is an angiogenesis cytokine in myeloma. This reminds me that one of my future projects is to create a permanent page listing all of these pro-inflammatory cytokines and their role in myeloma progression. Eh.

I would like to end today with a question: is there anything that we can do to inhibit IL-17? Or could we already be doing something? The answer to this question will be in tomorrow’s post. Oh, and tomorrow is "medical day." I am seeing my haematologist at noon (with a list of questions as long as the highway between Florence and Bologna), then my family doctor in the afternoon (shorter list of questions). I imagine I will have quite a long post tomorrow!

The dual nature of NF-kB

February 2, 2008 / / 2 Comments

This is the continuation of my January 22 post. From the Aggarwal (et al) NF-kB study, we know that when NF-kB “is found to persist in the nucleus, it is referred to as constitutive activation. […] The precise role of constitutive activation in tumors is not known but has been linked to resistance to apoptosis in human cutaneous T-cell lymphoma cells. It is tempting to believe that a similar mechanism accounts for the progression of all tumors that constitutively express NF-kB, but such a link has yet to be clearly identified.”

This entire section is interesting, actually, since it reports that another thing that has not been identified is the actual stimulus that renders NF-kB active all the time. What is clear, though, is that “Cells that express constitutively activated NF-kB are resistant to various chemotherapeutic agents and radiation treatment.”

And read this. In renal cell carcinoma (RCC) patients, “Serum C-reactive protein (CRP) elevation correlated with the increase in NF-kB activation; therefore, NF-kB may be a cause of the inflammatory paraneoplastic syndrome.” As we Myeloma Club members know, CRP reflects IL-6 activity and is thus an important marker for us. (My CRP, by the way, is within the normal range.) At any rate, I thought it interesting that this study reports a connection between high CRP and NF-kB. Well, well.

Another interesting quote: “Another virus that contributes to human cancer via NF-kB is the Epstein-Barr virus (EBV) implicated in Burkitt’s and Hodgkin’s lymphomas. The EBV nuclear antigen (EBNA)-2 and latent membrane protein (LMP)-1 enhance NF-kB activity thereby preventing apoptosis in EBV-transformed B cells.” While I was in grad school in Toronto, I tested positive for EBV. I was quite ill for about a month, tired all the time, etc., as I recall. Anyway, coincidentally (or…not?), a few years later I was diagnosed with MGUS. Well, I suppose it’s pointless to speculate, but this is not the first time I have read about the EBV-cancer link. Let’s proceed.

I found a fascinating study online (full study: http://tinyurl.com/2ntng6) titled “Good cop, bad cop: the different faces of NF-kB” that appeared in the January 2006 issue of “Cell Death and Differentiation.” It examines the different functions of this transcription factor, including that (drum roll!) of TUMOUR SUPPRESSOR. No kidding. NF-kB can promote both tumour growth and tumour suppression. Bad cop, good cop. How about that?

It is in this study that I read that NF-kB can be triggered by hundreds of “activators.” Hundreds? Parts of this study are barely intelligible, but I did manage to grasp a few basic concepts. The “classical” or “canonical” NF-kB pathway occurs when this transcription factor translocates, or moves, from the cytoplasm to the nucleus. This is when NF-kB gets activated by inflammatory cytokines such as tumour necrosis factor (TNF)-alpha and IL-1, in response, say, to a bacterial infection. The rest of that particular paragraph is not meant for non-scientific brains, for sure. So, skip, skip, skip! What matters is that at the end of this complicated process of activation, NF-kB ends up in the cell’s nucleus. This can occur in a matter of minutes. Amazing, eh? Then, once it has performed its good cop duties, under normal circumstances, NF-kB is escorted back (by a gene called IKB-alpha) to the cytoplasm, a process I mentioned briefly in my earlier post.

Then we have the “noncanonical” or “alternative” NF-kB pathway, which is activated by other kinases and, for instance, chemotherapy drugs. Some stimuli, such as UV-C (Short-wave ultraviolet radiation), activate NF-kB both by IKK-dependent and IKK-independent pathways. Ok, ok, my eyes are glazing over, too, and besides, I don’t want to get into too many details. Let’s stay focused on the main points.

Under certain conditions and in response to certain types of stimuli, it would appear that NF-kB can have proapoptotic effects. This “is consistent with the hypothesis that it is the mechanism of induction of NF-kB that determines its physiological function.” It’s all a matter of context, in other words. The important thing is that “If differences in the NF-kB response to a chemotherapeutic drug also occur in different tumors in patients or between patients with apparently the same type of cancer, the ability to more accurately diagnose NF-kB status could profoundly affect treatment choice and outcome.” (Apart from that unfortunate split infinitive, this is quite an interesting statement.)

We already know that NF-kB has pro-inflammatory effects. But the study shows that “NF-kB activity can also be required for the resolution of an inflammatory response. NF-kB activity in the later stages of inflammation has been associated with induction of anti-inflammatory genes and the induction of cell death. Moreover, inhibition of this late-stage NF-kB activity extended the length of the inflammatory response, inhibited the expression of p53 and Bax, and prevented apoptosis.” So sometimes NF-kB can reduce inflammation. I am not sure what late-stage NF-kB activity means, but the inhibition of the tumour-suppressing p53 gene is certainly not a good thing. More research needed.

Now read this shocker: “Because NF-B can perform a tumor suppressor function in some tissues, will its inhibition actually promote cancer in some situations?” Ouch!

The answer is: probably not, since treatment is “relatively short term,” and thus its inhibition of NF-kB would not have enough time to give rise to cancer. So the inhibition of NF-kB, the study states, seems to be the best approach to treating cancer. If the treatment were long-term, though, such as in the treatment of chronic inflammatory diseases, the “continuous suppression of NF-kB activity over a number of years could manifest itself in, for example, squamous cell carcinoma.”

This is a real head-scratcher. A "damned if you do, damned if you don’t" situation. I’d better stop here before my brain melts. But I have not finished with this topic. Not at all.

A quick update before I sign off to go feed the cats: since my so-so test results, I have introduced flaxseed oil capsules into my protocol, also because Sherlock is taking them, too. A slight change. I will update my protocol soon. Have a great weekend, everyone!

Be happy, but not TOO happy…(oh, and my test results…)

January 31, 2008 / / 8 Comments

The first part of my post title refers to a Science Daily article I read this morning while waiting, or fidgeting is more like it!, to drive to the hospital to pick up my blood test results: these refer to the tests that Sherlock and I took before beginning our biocurcumax experiment. More precisely, to the November-January period of my CMC (cocoa mass curcumin) experiment, when I was also taking a low dose, no more than the daily recommended dose, of Scutellaria baicalensis and Zyflamend.

A quick aside: you can read this rather interesting Science Daily "happiness" article here: http://tinyurl.com/2l38re In a few words, a new study suggests that "moderate happiness may be preferable to full-fledged elation." The “don’t be too elated” study seems quite appropriate in view of my current test results: yep, more seesaw results. I am getting used to going a bit up then down, so it’s no big deal, now that I have had time, a few hours, to process and digest the numbers. Ready? Ok, here goes.

My IgG went up from 27,80 to 31,90 g/L. Now, that’s not a huge jump in the wrong direction, but it’s still a jump, 12% or so. However (!), my m-spike went down slightly, from 2,20 to 2,17, and my monoclonal component decreased from 25,7 to 25 %. These aren’t huge changes compared to my previous tests, but I think the two itsy bitsy decreases are interesting. From what I understand, in fact, the m-spike and IgG count go down together, hand in hand, and vice versa. Perhaps I was fighting a cold or some sort of infection during those two months, so my good immunoglobulins increased. It’s very possible. Well, I won’t say any more on the matter until I speak with my hematologist next Wednesday.

Ok, first let’s get the negative stuff out of the way:

Ferritin ( = iron stores) is back to 7, down from last test’s 10 ng/mL. No worries, it has been that low. It will go back up.

My albumin is down from 49,5 to 48,2 %. Oh well. It’s been lower.

Beta-2 microglobulin went up to 1,9 from 1,6 mg/L. Still way within normal range, though.

Hematocrit went down a bit, from 39,5 to 37,4 g/dL. Hmmm. Well, it, too, has been lower.

Now for the good stuff:

My serum iron jumped from 62 (barely within the normal range) to 81 microg/dL. Guess all those steaks and spinach with lemon juice made a difference, after all!

Bence Jones is negative. For the blog readers who are not members of the very exclusive Myeloma Club: that’s good.

Total protein went down a teeny bit, from 8,8 to 8,7, creeping back toward the normal range (high end of the normal range is 8,6 g/dL). Good.

LDH, or lactate dehydrogenase, decreased from 158 to 146 U/L. Also good, since high levels of the LDH enzyme are associated with aggressive disease, which we do not want!

Creatinine is stable at 0,7, no change.

Calcium went down from 9,6 to 9,2 mg/dL. Still way within the normal range. Nice to see it go down a fraction.

CRP is still within the normal range. I hate it that I don’t get a number but only a “less than” value.

Oh, I almost forgot. All of my celiac disease tests were negative, and you know what that means: pasta for lunch!

Well, even though I know that the myeloma is still stable (Sherlock, whose mind is much more analytical than mine, confirmed my feeling), I admit that I am not the happiest camper in the world right now. I would have liked to have seen a drop in my IgG count, a substantial drop. But it’s true that my m-spike dropped a wee bit, and besides, the above-mentioned happiness study shows that, compared to blissfully happy folks, people who are only mildly happy have room for improvement. I like that. Furthermore, if you are completely happy and satisfied, you have nothing to wish for, as Sherlock wisely pointed out to me earlier today. And that is no fun. So, hey, every so-so test result has a silver lining, isn’t that the saying?

My questions, for now:

1. Did the Scutellaria baicalensis clash with the curcumin cocoa mix, even though I took them at different times of the day?

2. Did I take enough Scutellaria to make a difference? (Off the top of my head: probably not.)

3. Do tests taken in certain periods of the year yield similar results? (Work in progress.)

4. When I am testing one supplement, should I quit taking curcumin for a month or so, to see if said supplement really works by itself? Now there is a scary thought. It’s like asking the Peanuts character Linus to give up his security blanket for a month or so. Tremble tremble ! But, in the interest of science…who knows…I might consider it.

Sherlock and I agreed earlier that I should change over to the…atomic bomb, i.e. take biocurcumax the way she is: once a day, all in one gulp. Forget about tickling my myeloma cells with a half dose twice a day. My gut feeling right now is that I want to blast the blasted myeloma cells with the entire arsenal, i.e. the full dose. At this point, I should mention that I am a pacifist in real life, but when it comes to myeloma cells, well, I feel like crawling down my bone marrow with a bow and curcumin-containing arrow and hunt the malignant cells down one by one.

I am going to look over my tests this weekend, and Sherlock and I will come up with a plan for March. Tomorrow Stefano is driving to southern Italy with his parents and brother to make sausages and whatnot out of a poor dead pig (I tried to save the pig’s life, but was outnumbered…this is a long-standing family tradition), so I will be “alone” in Florence with the four kitties. Plenty of time to study this issue. And go play cards with my girlfriends. Life is good.

NF-kB: Dr. Jekyll or Mr. Hyde?

January 22, 2008 / / 6 Comments

A blog reader and I recently had an interesting exchange about this transcription factor, which is so important in myeloma…in a negative sense, unfortunately. Our discussion gave me the incentive to read more about it. My good friend Sherlock (grazie!) sent me a study published in January (2008) in “Experimental Biology and Medicine,” titled “Nuclear Factor-kB Activation: From Bench to Bedside,” and co-authored by Prof. B. Aggarwal (abstract: http://tinyurl.com/2m6j2g).

This transcription factor, discovered in 1986, was called NF-kB “because it was found in the nucleus bound to an enhancer element of the immunoglobulin kappa light chain gene in B cells.” Okay, wrap your brain around that! But seriously, if you reread the quote slowly, it begins to make sense: it’s a thingie (protein complex or transcription factor) sticking to the “kappa” gene inside a B cell’s nucleus.

Under normal circumstances, our immune system needs NF-kB to fight off diseases and infections. And until it is needed, this transcription factor follows my cats’ example and takes a lot of very long naps. I don’t want to go into its mechanisms of action (complicated stuff!), at least not today. Let it suffice that, once it has accomplished its task, it settles back down for another nap.

The study informs us that NF-kB is present in every type of cell, not just B cells as was first thought. Researchers have in fact discovered that it is located in the cytoplasm (the watery environment surrounding the cell nucleus) of all types of animal (from the fruit fly to us) cells. Another important finding is that it moves, or translocates, to the cell nucleus only when activated. Otherwise, it stays in, or (once it has finished its task) goes back to, the cytoplasm.

Things change with cancer. That’s when NF-kB turns into Mr. Hyde: it goes bonkers for a variety of reasons and ends up being active ALL the time, or constitutively active. And when this happens, NF-kB remains inside the cell nucleus, that is, it doesn’t return to the cytoplasm. No more naptime!

Skipping the technical parts about heterodimers, polyubiquitination and nuclear localization sequences (!), let me get to what we are really interested in: how does this transcription factor get activated in cancer cells? The study provides an answer: “NF-kB is activated by many divergent stimuli, including proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), epidermal growth factor (EGF), T- and B-cell mitogens, bacteria and lipopolysaccharides (LPS), viruses, viral proteins, double-stranded RNA, and physical and chemical stresses.” Radiation and chemotherapy also activate NF-kB. Speaking of which, the study tells us also that "Cells that express constitutively activated NF-kB are resistant to various chemotherapeutic agents and radiation treatment.” Vicious circle?

Another key sentence: “In tumor cells, different types of molecular alterations may result in impaired regulation of NF-kB activation. In such cases, NF-kB loses its transient nature of activation and becomes constitutively activated. This leads to deregulated expression of NF-kB– controlled genes.” NF-kB, the study continues, plays a critical role in cancer cell survival, inflammation, growth and so on. It regulates genes that are implicated in cancer cell proliferation, including TNF-alpha, IL-6, to name just a couple that we know are essential growth factors in multiple myeloma. It also regulates some of the cell cycle-regulatory proteins such as cyclin D1, also involved in myeloma (see my page on Ursolic Acid or my December 4 2007 post for more info on this gene, which has recently been associated with disease activity and progression).

Activated NF-kB is also implicated in the control of anti-apoptotic genes, that is, genes that keep cancer cells healthy and alive, such as survivin and Bcl-2 (again, see my post on ursolic acid). Furthermore, it regulates matrix metalloproteinases, or MMPs, which are proteases (protein-dissolving enzymes) that, among other things, promote cancer cell growth and angiogenesis. Okay, so there is no question that constitutively active NF-kB is not a good thing.

That’s enough for today, but I would like to end with a question: if we systemically inhibit NF-kB in order to stop our cancer from progressing, doesn’t that leave us more susceptible to infections? (More on this topic SOON!)

Margaret's Corner

Tag: myeloma