Sex, Lies and MyD88

Remember the movie Sex, Lies and Videotapes ? I saw that years ago, and rather liked it, as I recall. Oh, but here I just wanted a catchy title for my post, which actually has nothing to do with either sex or lies, but concerns MyD88, which is an intracellular signaling protein that carries signals from pathogen-associated molecules (translate: biological agents that can cause disease and illnesses, like parasites and viruses and bacteria) to IL-1, an inflammatory cytokine. Wikipedia defines MyD88 as: a universal adapter protein as it is used by all TLRs (except TLR 3) to activate transcription factor Nfkappa B. What are TLRs, you may ask? They are toll-like receptors, or proteins that play an important role (cytokine activation, for instance) in the immune system. I know, I know, this is not easy for me, either! But please bear with me. I do have a point or two to make. And at times I am swimming in very deep (very scientific!) water so if I make a mistake, please let me know.

Why am I writing about MyD88 today? Well, yesterday, as I was looking at the July 2007 issue of Science, my glance fell on this title: Sex, Cytokines and Cancer (http://tinyurl.com/2sq9v6). I must admit that if that article had been titled, e.g., MyD88 and Cancer, I probably would not have been intrigued enough to read it. What can I say? I too like to have a bit of fun with catchy titles, as you may have noticed 😉

The first part of the article deals with the relationship between cancer and inflammation. It’s an interesting read, so I urge you to go have a look. The authors then examine two studies, published in the same issue of Science. The first, by Naugler et al (see: http://tinyurl.com/237wfb), discusses the link between gender and liver cancer, and the fact that estrogen is an IL-6 inhibitor, which I did not know. The second, by Rakoff-Nahoum and Medzhitov (http://tinyurl.com/2bu9nr), is a study on intestinal cancer. These two researchers discovered that MyD88 stimulates the overexpression of COX-2 and of IL-1, suggesting that this protein promotes and also thrives on cancer. Well, I looked up IL-1 and discovered that it happens to be a MM cell growth promoter, as can be seen in this 2006 Oncogene study: http://tinyurl.com/2wp4sb Indeed, according to another 2006 study (http://tinyurl.com/3294yj), published in the Journal of Interferon and Cytokine Research, IL-1 it is a potent inducer of the important myeloma growth factor, IL-6. This particular study, which compared groups of SMM and active MM patients with low or high IL-1 production, was interesting for another reason. The researchers found that when IL-1 was inhibited, the production of IL-6 in most patients dropped by 90%, leading them to the conclusion that it may be possible to predict patients that will progress to active MM and to delay or prevent this progression with IL-1 antagonists.

DELAY or PREVENT progression? My dream come true!

At this point, a flickering light bulb went on in my head, and I looked up MyD88 and curcumin. Sure enough, curcumin apparently prevents this protein from going about its nasty business. A July 2007 study (http://tinyurl.com/33cjlc), published in the Journal of Leukocyte Biology, discusses bacterial infections and curcumin, and concludes that curcumin inhibits the MyD88-dependent and -independent signaling pathways of LPS signaling through TLR4 [ ]. LPS, by the way, stands for lipopolysaccharide, an endotoxin found inside pathogens (bacteria, e.g.), and TLR4 is another of those above-mentioned toll-like receptors (see Wikipedia for more information on TLRs: http://tinyurl.com/3demwz). A June 2006 study published in Biochemical Pharmacoloy (http://tinyurl.com/2tvjnu) shows that curcumin inhibits both MyD88- and TRIF-dependent pathways in LPS-induced TLR4 signaling. (Note: TRIF, or TIR-domain-containing adapter-inducing interferon-β, is a signalling pathway that is active mainly in the spleen and is dependent on MyD88.). Oh, and by the way, curcumin downregulates the expression of IL-1, too. A more detailed discussion can be found in Prof. Aggarwal’s 2006 study titled “Spicing Up of the Immune System by Curcumin,” which I would be happy to forward upon request.

I also discovered that EGCG has the same blocking effect of curcumin against MyD88 (see: http://tinyurl.com/2lrh8r): green tea flavonoids can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs and subsequent inflammatory target gene expression. Now how about that? All this makes me wonder how many more non toxic phytochemicals can inhibit MyD88 ? When I have more time, I must look into this matter more carefully.

Concluding remarks. For the non-scientists among us, this appears to be gibberish, but the basic point is that here we have a couple of non toxic substances €”curcumin, EGCG €”that inhibit the activity of a protein, MyD88, essential for the activation of NF-kB. No MyD88, no NF-kB. It seems to be that simple! So if we can block the activity of this signalling pathway, we can also block the effect of inflammatory cytokines that are important, indeed, crucial, for MM cell proliferation and survival. This tiny bit of research (and I barely revealed the tip of the iceberg, there were more studies to be had on this topic, but unfortunately my time is extremely limited today) has given me another reason to keep taking curcumin, and to add EGCG to my future supplement list.

Eat Liquorice…In Moderation

I recently came across a rather curious item called glycyrrhizin, which is extracted from the root of liquorice, or Glycyhrrhiza glabra, a plant native to Turkey, Iraq, Spain, Greece and northern China. According to Wikipedia, it is 30-50 times as potent as table sugar. But it is not merely a sweetener. In ancient Greece, China and Egypt (see the MD Anderson write-up: http://tinyurl.com/2ylhja), liquorice was used to treat gastritis, coughs and colds. The MD Anderson summary gives an interesting bit of the history of liquorice; for instance, in ancient Egypt a liquorice drink was used to to honor spirits of the pharaohs, and then during World War II a Dutch physician discovered that it was effective against peptic ulcers. I should note that the liquorice FAQ page has not been updated since 2005 but is still informative (side effects, dosage and whatnot).

Glycyrrhizin is the active ingredient of liquorice root: it has anti-viral activity, ranging from the flu virus to herpes simplex and even hepatitis B and C; liver-protective (hepatoprotective) effects, and anti-HIV activity. It also clears up microbial and parasitic infections, is a thrombin inhibitor (see: http://tinyurl.com/364qr4), and is effective against allergies, chronic fatigue, asthma, arthritis and free radicals, just to give a few examples. Oh, and how about this for an interesting titbit (see: http://tinyurl.com/3yx72p)? Glycyrrhizin inhibits the replication of the SARS virus (remember that scare a few years ago?). It also apparently inhibits NF-kB and has anti-inflammatory properties. Very good. Nope, no studies on glycyrrhizin and MM cells. Too bad. However, there are other studies, so here follows a bit of a laundry list.

A June 2007 study (http://tinyurl.com/2mr62v) examines the cytotoxicity of glycyrrhetinic acid (GA) in combination with dehydrozingerone (DZ). The latter is extracted from ginger and possesses anti-inflammatory and antioxidant properties. I am going to do more research into this particular combination, but for now, I will leave it at that. When combined, these two conjugates were found to have potent cytotoxic activity ; however, when administered separately, they “were inactive.” An August 2007 study (http://tinyurl.com/38rhx3) examined sixteen GA derivatives and determined which had the strongest anti-proliferative and apoptotic effects against the previously-seen HL-60 leukaemia cells. This apoptotic effect on HL-60 cells had already been observed, as can be seen in this 2005 study: http://tinyurl.com/28osnh A 2006 study (http://tinyurl.com/3yd7q8) looked at the effects of a glycyrrhizin extract on human hepatoma, promyelotic leukemia and stomach cancer cells. Apoptosis was again the result.

A 2005 study (http://tinyurl.com/2sssqa) states that Glycyrrhetinic acid (GA) and its related compounds are known to have anti-inflammatory activity and also to inhibit liver carcinogenesis and tumor growth. It concludes that GA may be important in the treatment of liver cancer. Another 2005 study (http://tinyurl.com/38oszl) shows that GA protects our bodies from the damage caused by UVB radiation, but has no effect on metastatic melanoma cells. A 2001 study (http://tinyurl.com/2sc6nv) tells us that Glycyrrhizic acid is an inhibitor of lipoxygenase and cyclooxygenase, inhibits protein kinase C, and downregulates the epidermal growth factor receptor. Licorice polyphenols induce apoptosis in cancer cells.

This is all very interesting, and there seems to be a lot of apoptosis going on, but, and there is a but!, it appears that ingesting too much glycyrrhizin may not be such a good idea if you suffer from hypertension, heart disease or have water retention problems (you can read more about that in the MD Anderson FAQ page). In fact, this German Senate Commission on Food Safety report (http://tinyurl.com/2tor53) recommends that no more than 100 mg should be ingested per day on a regular basis. High doses of this compound may also reduce potassium levels. Of course, we MMers don’t want that to happen!

Final note. There is a type of liquorice without glycyrrhizin, known as Deglycyrrhizinated liquorice or DGL. So you can still enjoy the taste and some of the benefits without any unwanted side effects. And the following just occurred to me: some curcumin-takers have reported having gastric problems after ingesting curcumin well, how about trying some liquorice to settle your stomach? And here is a thought (to be discussed with your doctor, of course) for those doing chemotherapy or about to have a SCT: taken in powder form mixed with water (as a mouthwash), I read that DGL can be effective against mouth ulcers. It can also can help prevent nausea and vomiting. I don’t like the taste of liquorice, actually, but if some day a study proves that it has an anti-MM effect, I will be running to the nearest…liquorice store!

Fragments of My Life

Where does time go? I seem to have no time to do anything, these days! Well, okay, I do spend a lot of time with Peekaboo, our new kitten (but also with my older cats, otherwise they’d turn green with jealousy). By the way, the word “peekaboo” means nothing in Italian. The Italian equivalent would be something like “bubusette!”

Kitten health update: yesterday my Mom and I took her to the vet who said that she no longer has ear mites or fleas (yeah!), so the only thing that keeps her from being introduced to our older cats are the crummy intestinal parasites. So little Peekaboo will remain in quarantine for another couple of weeks. A very happy, bouncy and friendly kitten, she is currently trying to learn how to fly. We have tried to arrange the furniture so that she won’t hurt herself by missing one of her audacious jumps (on at least two occasions I have seen her sail through the air toward her goal–the desk–and crash to the ground; she is completely fearless!). Of all of her wonderful cat toys (passed down by the older ones, unbeknownst to them!), the one she likes the most is a stupid old champagne cork attached to a piece of string. Typical. 🙂

I promised to blog some personal news, so here goes. I already wrote that I am a U.S. citizen, a permanent resident of Italy, married to a tall dark handsome wonderful Italian. But I don’t think I mentioned that I grew up here, yes, right here in Firenze. My parents moved here when I was barely out of kindergarten. I attended the American School of Florence for a couple of years, but my parents transferred me to an Italian public school when I was eight years old. I am completely bilingual: I speak, read and write in both languages fluently. No accent in either, even when I switch back and forth quickly.

I don’t remember much about learning Italian. My elementary school teacher used to assign work to the other children in order to have the time and concentration to teach me this new language. My schoolmates, as I recall, never made fun of me or considered me to be an odd creature speaking an odd-sounding language. They didn’t shun me at all, as you might expect from kids that age. On the contrary, they were very friendly and helpful, and thanks to them I learned Italian more quickly. After three months, my mother reports, I was writing compositions in Italian on the Punic Wars. I went through the entire Italian school system, but when I was in my second year at the university of Florence my parents decided to move back to the States. I decided to go with them. I worked and studied in the U.S. and Canada for several years, but, to be honest, I was miserable. Don’t get me wrong, I love the States and of course I love and miss my family. Peekaboo July 27 2007But home is where your heart is, right? Well, my home has always been Florence. I always felt that I would end up here, somehow. And in fact, while I was in Florence doing research for my Ph.D. thesis, a few conniving 😉 mutual friends introduced me to my husband. We moved in together less than a year later, just a few months after I was awarded my Ph.D. We have been together for more than 11 years, and counting!

Ok, enough for today. It is time for me to join Stefano and our new kitten (I took this photo yesterday, by the way) downstairs. Oh dear, I hope I haven’t bored y’all to tears! 😉

Raise Your Glass To Fight Gum Disease!

A lot has been written about the healthful compounds contained in wine, red wine in particular. For us MMers, the most important compound is resveratrol, which is an MM-cell killer in vitro. See my page on resveratrol for more information. And other wine polyphenols have antioxidant properties, too. Of course, since you would probably have to drink a case of wine or more to get enough polyphenols to make any difference, capsules containing the concentrated form are the way to go. However, if you only have gum disease, apparently just a little bit of wine can make all the difference.

I recently read a June 2007 University of Pavia abstract on wine and oral bacteria. These Italian researchers found that wine kills streptococci, the nasty bacteria which can cause sore throats, cavities and tooth decay (I didn’t know that until I read this abstract!). Interestingly enough, wine’s phenolic compounds (tannins and anthocyanidins) did not produce such an effect. What turned out to kill the nasty streptococci were the organic acids in wine, specifically: succinic, malic, lactic, tartaric, citric, and acetic acid (see: http://tinyurl.com/2vqmkl) Taken separately, in a concentrated form, these acids had an almost 100% success rate against eight streptococci strains, whereas when when mixed in with wine (which is the way we would imbibe them), their killing effect was not as powerful. However, even a small amount of wine was found to inhibit the proliferation of the harmful bacteria.

A Canadian study published in 2006 had already examined the effects of grape seed extract on gingivitis and periodontal disease: http://tinyurl.com/2sb9go The abstract concludes that proanthocyanidins have potent antioxidant properties and should be considered a potential agent in the prevention of periodontal diseases. So, those who enjoy a bit of wine with dinner have another excuse to raise their glasses!

Confession: I rarely drink wine, even now that I know that it contains resveratrol. I really don’t care for the taste, unless it’s a really special wine, like a nice Brunello di Montalcino served in a proper wine glass at the proper temperature etc. And I live in Tuscany, the region of wonderful Chianti…oh dear, what can I say? 🙂

A final comment: I read that these wine acids may weaken our tooth enamel. So I guess that I will put off learning to love the taste of a good Chianti for a while yet. In the meantime, I am dashing off to brush my teeth. 😉

The Sixth Sense of Cats

My brother-in-law just sent me an extraordinary article printed in the Italian Corriere della Sera today. As a huge cat-lover, I just had to post this piece. For those of you who read Italian, see: http://tinyurl.com/2yu4e7 Everyone else, read these excerpts from the current issue of the New England Journal of Medicine (no kidding!). The entire article can be read at: http://tinyurl.com/2kaw5l The photo of Oscar, by the way, was taken from Albany’s Timesunion: http://tinyurl.com/3cppyo I have read stories of dogs having these uncanny abilities, but this is the first time I have read one about a cat. Since I don’t want to spoil this mind-boggling albeit rather morbid account, I will stop here, but if you are easily spooked, do not read any further. Just a note: this cat looks very much like my sweet Puzzola!

A Day in the Life of Oscar the Cat

David M. Dosa, M.D., M.P.H.

Oscar the Cat awakens from his nap, opening a single eye to survey his kingdom. From atop the desk in the doctor’s charting area, the cat peers down the two wings of the nursing home’s advanced dementia unit. […] Slowly, he rises and extravagantly stretches his 2-year-old frame, first backward and then forward. […] In the distance, a resident approaches. It is Mrs. P., who has been living on the dementia unit’s third floor for 3 years now. […] She passes him without a glance and continues down the hallway. […] Oscar decides to head down the west wing first, […] continues down the hallway until he reaches its end and Room 310. The door is closed, so Oscar sits and waits. He has important business here.
Death CatTwenty-five minutes later, the door finally opens, and out walks a nurse’s aide carrying dirty linens. “Hello, Oscar,” she says. “Are you going inside?” Oscar lets her pass, then makes his way into the room, where there are two people. Lying in a corner bed and facing the wall, Mrs. T. is asleep in a fetal position. Her body is thin and wasted from the breast cancer that has been eating away at her organs. She is mildly jaundiced and has not spoken in several days.
[…] Oscar […] leaps up onto the bed. He surveys Mrs. T. She is clearly in the terminal phase of illness, and her breathing is labored. Oscar’s examination is interrupted by a nurse, who walks in to ask the daughter whether Mrs. T. is uncomfortable and needs more morphine. The daughter shakes her head, and the nurse retreats. Oscar returns to his work. He sniffs the air, gives Mrs. T. one final look, then jumps off the bed and quickly leaves the room. Not today.

Making his way back up the hallway, Oscar arrives at Room 313. The door is open, and he proceeds inside. Mrs. K. is resting peacefully in her bed, her breathing steady but shallow. […] Oscar jumps onto her bed and again sniffs the air. He pauses to consider the situation, and then turns around twice before curling up beside Mrs. K. One hour passes. Oscar waits. A nurse walks into the room to check on her patient. She pauses to note Oscar’s presence. Concerned, she hurriedly leaves the room and returns to her desk. She grabs Mrs. K.’s chart off the medical-records rack and begins to make phone calls. Within a half hour the family starts to arrive. […] Thirty minutes later, Mrs. K. takes her last earthly breath. With this, Oscar sits up, looks around, then departs the room so quietly that the grieving family barely notices.

On his way back to the charting area, Oscar passes a plaque mounted on the wall. On it is engraved a commendation from a local hospice agency: “For his compassionate hospice care, this plaque is awarded to Oscar the Cat.” Oscar takes a quick drink of water and returns to his desk to curl up for a long rest. His day’s work is done. There will be no more deaths today, not in Room 310 or in any other room for that matter. After all, no one dies on the third floor unless Oscar pays a visit and stays awhile.

Note: Since he was adopted by staff members as a kitten, Oscar the Cat has had an uncanny ability to predict when residents are about to die. Thus far, he has presided over the deaths of more than 25 residents on the third floor of Steere House Nursing and Rehabilitation Center in Providence, Rhode Island. His mere presence at the bedside is viewed by physicians and nursing home staff as an almost absolute indicator of impending death, allowing staff members to adequately notify families. Oscar has also provided companionship to those who would otherwise have died alone. For his work, he is highly regarded by the physicians and staff at Steere House and by the families of the residents whom he serves.

Harry’s Here!

Peekaboo and Harry Potter, July 23 2007In my excitement at having received my Harry Potter book yesterday morning, I forgot to publish this draft. Duh! So I will post it today, together with an update. First, the post that didn’t get posted yesterday:

July 23: I was just about to write my research post of the day when the doorbell rang. UPS just delivered my U.S. copy of Book 7 in the Harry Potter series. I could have bought the British edition here last Saturday when the book was released, but since I bought (and loved!) my first Harry Potter books in the U.S. before they became so amazingly popular, I didn’t want to break with…tradition, even if it meant waiting a few extra days to read it. Anyway, that was really FAST! I expected the package to arrive on Wednesday at the very earliest. By the way, the expedited international priority delivery cost more than the book itself (but was well worth it!).

Since Saturday morning, I have avoided reading any news on Internet, I have not read one single newspaper, and I have not watched or listened to any news. Sounds ridiculous, but I hate to know how a book ends before I read it (I never flip to the last page, no matter how curious I am), and I knew that the end of this saga would be broadcast all over the place. It was. Even my parents (who did watch the news), who are not Harry Potter fans, know how Book 7 ends! Anyway, I am glad to say that I still have NO idea what happens, so I am going to retreat downstairs with Peekaboo now and bury my nose in the book. Forget my post. I will think about that tomorrow.

I have probably just undermined my credibility as a serious researcher, but, as we say in Italy, pazienza! 😉

July 24: I am more than halfway through the HP book, in spite of Peekaboo distracting me by trying to chew on and tear the pages and batting furiously at the images inside the book. When she gets tired, she reads the book with me, as you can see from the photo. I will post something more serious tomorrow. Today I have to finish this book!

Phenethyl Isothiocyanate

I wrote a post on broccoli back in April, but only recently came across some more info that I thought I would discuss briefly today. It’s about a substance contained in cruciferous vegetables (in addition to broccoli, also: cauliflower, kale, cabbage, watercress, radishes, and arugula or rucola, which by the way is also rich in vitamin C and iron, etc.) called phenethyl isothiocyanate, more familiarly known as PEITC, which has chemopreventive properties. According to a 2005 University of Pittsburgh study (http://tinyurl.com/2p52nh), Evidence is accumulating to indicate that PEITC can suppress proliferation of cancer cells in culture by causing apoptosis and/or cell cycle arrest [ ]. Growth inhibition, apoptosis induction, and/or cell cycle arrest by PEITC has been noted in human leukemia, prostate, myeloma, hepatoma, and colon cancer cells. Please note that myeloma is mentioned in the same breath as the following words: cell arrest, apoptosis and growth inhibition! PEITC inhibits NF-kappa B and activates the tumor suppressor p53, among other things. This is all very good news. I will attempt to get my hands on the specific study citing MM cells affected by PEITC this fall.

A study published in the 2000 issue of Biochemical Pharmacology (http://tinyurl.com/2hmeu5) states that The dietary isothiocyanates and cancer chemopreventive agents phenethyl isothiocyanate and allyl isothiocyanate and their cysteine conjugates inhibited the growth and induced apoptosis of human leukaemia HL60 (p53 ˆ’) and human myeloblastic leukaemia-1 cells (p53+) in vitro. And a study published in Cancer Research in 2007 (http://tinyurl.com/ywk4yw) shows that PEITC has an effect on angiogenesis: the present study suggests that inhibition of angiogenesis may be an important mechanism in cancer chemoprevention by PEITC.

I also found a couple of studies on the combined synergistic effect of curcumin and PEITC on prostate cancer. A 2005 study (http://tinyurl.com/32gz8b) published in Carcinogenesis showed that this dynamic duo exerted a more potent effect on prostate cancer cells when administered together rather than apart. They also had apoptotic effects on these cells. A 2006 Cancer Research study confirmed that this combination significantly slowed the growth of tumours, but this time in vivo (mice), whereas the effect was minimal when both substances were administered separately. Another study on PEITC and prostate cancer cells (http://tinyurl.com/29zljl), published in 2004, is interesting because it mentions that PITC, a PEITC analogue, didn’t have any anti-cancer effects: These results indicated that even a subtle change in isothiocyanate (ITC) structure could have a significant impact on its biological activity. This particular sentence inspired me to write about a doubt that I have had concerning curcumin analogues. I think I mentioned this in a previous post, probably when I was discussing the issue of nanocurcumin, but at any rate, here it is: by fiddling around with these molecules, don’t we risk altering them too much for them to provide any anti-cancer benefits? Is it possible that the more we stray from the original extract, the more we may diminish its effectiveness? Am I way off base here? My non-scientific brain cannot provide any answers, of course.

Peekaboo, July 21 2007There are many other studies on PEITC and different cancers, but this post was beginning to look like a laundry list, so I cut most of it. However, those interested in seeing my rather large PEITC file can drop me a note and I will gladly forward it.

I would like to end by saying that I have been asked to give more information on my day-to-day life. So I will be doing that from time to time. Bits and pieces from what I consider to be my rather boring life. Oh, wait, how can life be boring with a new kitten in the house??? 🙂

Precious Peekaboo

Peekaboo, July 20 2007At the risk of turning my blog into a temporary cat blog 😉 I am going to post a couple of the most recent photos of my new kitten, Peekaboo. The first of a series, I am afraid! 😉 Ah yes, I didn’t do any research yesterday (or today, for that matter) because we picked her up yesterday morning. Who can think of doing anything serious with a new kitten in the house? Plus, we need to monitor her closely because she is suffering from horrid intestinal parasites and ear mites (typical of outdoor kitties). We are treating her for this crappy (literally) stuff, of course. The vet told us that we wouldn’t be able to introduce Peekaboo to our other cats for a month or so. She has to be “quarantined” until she is completely rid of the nasty creatures. So we have created a feline entertainment centre for her down in our TV room, which is a long room with plenty of space for her to play and run around, and comfy chairs where she can sleep (when human bodies are not provided as cushions). Peekaboo, July 21 2007Yesterday, after we brought her home from the vet, she went nuts over all her new cat toys, which range from simple Chianti wine corks (my Priscilla’s favourite!) to rubber balls that glow in the dark and scratching “trees.” Etc. Too much fun. She ran around like a mad thing, climbed all over the chairs and us, took several tumbles, etc. Then she conked out on my chest. Today she seems even more exhausted, in part because the medicine is beginning to work (probably), so right now she is lying on my husband (see photos). He is absolutely thrilled, because our other cats never really curled up on him. Peekaboo hasn’t budged from his chest since we had lunch, about three hours ago, and he hasn’t moved an inch, either! Oh dear, I had better move my computer downstairs, or I won’t get any research done for the next century or so! 😉

The Importance of Saying the Right Thing at the Right Time…

First, I would like to thank everyone who sent me birthday messages in various forms (e-cards, photos of beautiful flowers, e-mails etc.). No way I can answer every single message, but I want you all to know that I appreciated everything! Grazie!

A friend (thanks!) sent me a joke that gave me a good chuckle yesterday. Keep ’em coming! 🙂 Here goes:

The morning after attending his company’s anniversary party, Jack wakes up with a huge hangover. He doesn’t even remember how he got home from the party. He is troubled by a vague feeling that he did something wrong.

He forces himself to open his eyes, and the first thing he sees are a couple of aspirins and a glass of water on the bed table. He sits up and sees his clothing laid out in front of him, clean and pressed.

He looks around the room and notices that it is in perfect order, spotless and tidy, as is the rest of the house. He takes the aspirins, but then cringes when he sees a huge black eye staring back at him in the bathroom mirror.

Then he sees a note stuck to the corner of the mirror: “Honey, breakfast is on the stove, I left early to get groceries to make you your favorite dinner tonight. I love you, darling! Love, Jillian”

He staggers into the kitchen, and sure enough, there is a hot breakfast, steaming hot coffee and the morning newspaper. His son is also at the table, eating.

Jack asks, “Son…what happened last night?”

“Well, you came home after 3 A.M., drunk and delirious. You fell over the coffee table and broke it, you were sick in the hallway, and you got that black eye when you stumbled into the door.”

Confused, he asked, “So, why is everything in such perfect order and so clean, and breakfast is on the table waiting for me???”

His son replies, “Oh THAT!… Mom dragged you to the bedroom, and when she tried to take your pants off, you yelled, “Lady, leave me alone, I’m married!!!”

Quercetin and Oncogenic RAS: No Gas, No Growth!

I have just linked a couple of news items €”on quercetin and oncogenic RAS €”whose consequences may be significant to us MMers. Before I go on, though, what is this RAS business? Simply put, RAS is a gene that can mutate and become overactive, leading to the development of cancer. In this dangerously altered state, it is known as oncogenic RAS, and is present in almost one-third of all cancers, according to a recently published Duke Medical news release, see http://tinyurl.com/34x3oo. According to these Duke researchers, attempts at inhibiting this mutated form of the RAS gene have failed so far. Therefore, they looked at inhibiting the cytokine activated by oncogenic RAS, and guess what? That cytokine just happens to be Interleukin-6 (yes, our infamous pro-inflammatory IL-6!). The Duke University researchers also found that angiogenesis was reduced by inhibiting the production of IL-6, and that “‘IL-6 was like the gas pedal driving the growth of tumors,’ Counter said. ‘No gas, no growth, which is exactly what we saw when we inhibited IL-6 in tumors.’ Counter is encouraged that even though these findings are in cell culture and animal models, therapies based on targeting IL-6 in cancers driven by the ras oncogene could be tested in humans in the near future. [ ] A phase II trial is underway testing a monoclonal antibody against IL-6 for patients with multiple myeloma, a cancer that depends on IL-6 but is not known to have a connection to the ras oncogene. If the results of this trial are positive, studies might begin in ras-dependent cancers. Counter’s group is actively pursuing the idea that such an antibody may inhibit pancreatic cancer growth in mouse models. If these results are positive, this will open the door for Duke oncologists to organize a clinical trial to test the agent in human cancer patients.” The abstract of the Duke study can be read here: http://tinyurl.com/23merm

The question then arises: is oncogenic RAS present in MM? As you may have guessed from the above-mentioned Duke Medical news release, the answer is: yes, it is, in a certain percentage of patients which seems to vary from study to study. Not surprising, I would add, since we are all so different. A 1992 study (http://tinyurl.com/ytb863) showed that RAS gene mutations were present in 47% of the MM patients (14 out of 30 patients). I thought the following finding was significant: RAS gene mutations were more frequently observed in patients with fulminating disease (10/15, 67%) than in patients with less aggressive forms of the disease (4/15, 26%). So, oncogenic RAS seems to be connected to a more aggressive form of MM. This would appear to be confirmed by the results of a 1989 study (http://tinyurl.com/yux83g): While the mechanism of occurrence and biological role of ras activation in MM remains to be elucidated, the preliminary correlations observed in this study between the presence of ras oncogenes and poor therapeutic response suggest that further investigations of the possible prognostic significance of these alterations are necessary. According to a more recent Italian study, published in March 2007 (http://tinyurl.com/2bfugg) Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). These mutations were detected in 20% of 81 newly diagnosed MM patients. The abstract concludes, however, that these mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities.

Another study, published in Blood in 2003 (full study: http://tinyurl.com/23e48r), looks at pathways activated by oncogenic ras that may stimulate IL-6-independent growth, and concludes: In summary, we have identified several signal pathways in myeloma cells constitutively activated by expression of mutated ras genes. Our results also suggest that these pathways provide excellent molecular targets for future therapy.

Why am I writing about this today? Because I just finished reading a study titled Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha-RAS-transformed human colon cells and published in Carcinogenesis in May 2007 (abstract: http://tinyurl.com/22byoz; full text: http://tinyurl.com/23clc8) showing that quercetin downregulates the levels of oncogenic RAS in cancer cells. How about that? The study suggests that quercetin be used in cancers with frequent mutations of RAS genes. Interestingly enough, quercetin inhibits oncogenic RAS but not normal RAS. Excellent. Sure, this study is about colon cancer cells, but I think the implications could apply to MM as well, given the IL-6 connection. Therefore, I believe we MMers have another GOOD reason to keep taking quercetin (or to start taking it!). Indeed, I couldn’t have received a better birthday present (except the news that J.C. Rowling has decided to continue writing more chapters in the Harry Potter series! 😉 )