Monthly Archives: November 2009

Cucumbers and…multiple myeloma?

You know the bitter taste that you get in your mouth sometimes after biting into a slice of cucumber? Well, years ago my mother showed me how to get rid of that rather bothersome taste, but I won’t be using her method anymore…nope, not after reading what I read earlier today.

The above-mentioned bitterness is caused by a…bitter group of chemicals called cucurbitacins. The more cucurbitacins contained in your cucumber (or any member of the Cucurbitaceae family…melons, pumpkins, squash etc.), the bitterer the taste. The bitterness gives us a sort of warning not to eat the cucumber. But if we are hungry or stubborn enough to ignore the warning, we could develop stomach cramps or worse: back in the 1980s, there were more than 200 cases of zucchini poisoning (!) in Australia, Alabama and California. So: beware of bitter…it could be toxic!

You are probably asking yourselves why I am so interested in this cucurucu-stuff today. Well, it turns out that the cytotoxic properties of all the cucumber family members could be put to good use. This morning a blog reader (thank you!) sent me the link to a study that mentions the fact that cucurbitacins are STAT3 inhibitors, see: http://tinyurl.com/ye3cfmp She also sent me the full study where I found this titbit: Another class of STAT3 inhibitors includes natural products and their derivatives with anti-tumour activities, such as cucurbitacin, resveratrol, galiellalactone, curcumin and indirubin. The molecular mechanisms of action of these natural product inhibitors, which probably inhibit other oncogenic signalling pathways in addition to STAT3, remain to be fully determined.

Since STAT3 is an important signaling pathway in multiple myeloma, I did a quick search of PubMed for studies on cucurbitacins and myeloma. Bingo! I found the abstract of a paper presented at the 2007 ASH annual meeting, see http://tinyurl.com/y9hzgr4 The title says it all: Cucurbitacin I (JSI-124) Has Potent Anti-Myeloma Effects Independent of Its Inhibition of JAK2-Induced STAT3 Activation. I don’t have the full study yet, but there is enough in the abstract to hold our attention: several multiple myeloma cell lines were ultimately trampled to death by JSI-124, or Cucurbitacin I.

This plant extract is identified as a powerful direct inhibitor of myeloma cells blocking constitutive and IL-6/BMSC-dependent STAT3 activation in addition to STAT3 independent signaling pathways. This is clearly excellent news. And there is more: this substance targets both the malignant myeloma cell AND its bone marrow microenvironment, which, as we know by now, is crucial for the cell’s development, growth and survival. A double whammy for our myeloma cells…

Well, this has certainly given me a new appreciation for…cucumbers!

More on the importance of Vitamin D

I have been feeling unusually weary in the past few (several?) days, so I have been taking it easy whenever possible. As a result, I have ignored the blog and haven’t done any research or finished editing any of my drafts.

About half of my students are convalescent, coughing germ-factories 😉 As for me, I have no flu symptoms, just this bothersome fatigue and occasional night sweats, which might be caused by an inner battle with some sort of virus. So the other day, just to give my immune system a little boost, I began taking two teaspoonfuls of Sambucol. I don’t know what is causing my tiredness, but I am not concerned: it gives me a good excuse to lie down during the day and catch up on my reading, surrounded by sleeping or purring cats…

Today I thought I would post the link to a November 24 Science Daily article on vitamin D, which, by the way, I take on a daily basis (in the form of cholecalciferol/vitamin D3). Don’t forget to read the next-to-last paragraph on heart disease: http://tinyurl.com/ylavp4x Ah, and one last thing: please be careful not to take too much vitamin D: http://tinyurl.com/b92tnz

National Curry Week!

November 22-28 is “National Curry Week” in the UK. Ah, how I wish I could be there! A Google Alert this morning took me to an interesting Liverpool Echo article (http://tinyurl.com/ydmobdo), which includes information on turmeric, chilli, garlic and ginger (and a curry recipe, too, on page 2). No need for me to comment on turmeric, right? And we are well aware that the capsaicin in chilli kills myeloma cells…and so does a ginger extract (see my Pages on the right).

But garlic? I haven’t written much about garlic (shame on me!). Apart from its well-known general health benefits (http://en.wikipedia.org/wiki/Allicin), I found several studies in PubMed on its keema-curry[1]anti-leukemia activity…hmmm, nothing specific about garlic and myeloma, but that simply means, methinks, that garlic extracts have not yet been tested against myeloma cells. If I were a researcher, I would request a grant to study this very topic, since I am almost 99.99999% positive that garlic would annihilate myeloma cells, too. Wanna bet?

Just out of curiosity, have a look at these two garlic-leukemia studies (I picked a couple at random, but there are many more on PubMed): (2004) http://tinyurl.com/ycxq7dh and (2009) http://tinyurl.com/yegomal. Incidentally, in the former, a garlic-derived compound called ajoene enhanced the killing effect of two chemo drugs used in the treatment of hematological malignancies: cytarabine and fludarabine. Now, that bit of news could easily set me off on my usual rant about how the only way we will be able to defeat cancer is via a combination of conventional and natural treatments…but I will refrain…today, at least! 

Now, back to National Curry Week for a moment. Ever since I found out about the healing properties of turmeric and other curry spices, I have been making delicious curry dishes, mainly in the winter. Curries are easy to make and relatively fast, once you are experienced enough to stop measuring exact quantities…now I simply glance at the recipe and throw in the spices, e.g. Another advantage of curries is that you can make them a day ahead…so they are perfect for dinner parties! In sum, I hope my UK readers will enjoy Curry Week! Yummy!

P.S. Here is what seems to be an interesting garlic-cancer (full) 2008 study: http://tinyurl.com/ye85asa (I haven’t read it yet, but I will!).

Chocolate eases emotional stress

On Sunday I played cards in a charity tournament, which meant being in a large room for several hours with at least 50 other card players and yes, some of them were coughing up a storm. I was very careful never to touch my face, of course, but I had to breathe! Then on Tuesday one of my students told me that she had had a high fever the previous night. She looked terrible and was still having chills alternating with sweats. I told her to go home immediately, but she said she had too much work to do. Sigh.

Well, this combination was probably a bit too much for my itsy bitsy immune system. Yesterday morning I woke up a headache, a bit of nausea, and, drum roll!…chills alternating with sweats. I slept for most of the day, surrounded by my devoted kitty nurses. I didn’t have a fever, so I think this must have been some sort of 24-hour minor bug…not H1N1 or even the regular flu. I feel fine this morning, in fact.

Okay, now for an infinitely more interesting topic. A recent Science Daily article reported on the results of a dark chocolate and stress clinical trial (see: http://tinyurl.com/y8jqd7a): The study provides strong evidence that a daily consumption of 40 grams [1.4 ounces] during a period of 2 weeks is sufficient to modify the metabolism of healthy human volunteers. This amount of chocolate reduced levels of stress hormones in the bodies of people feeling highly stressed. Well, this is more good news for those of us who enjoy a bit of chocolate especially since, as you may recall, the stress hormone norepinephrine makes our myeloma cells proliferate like crazy (for a reminder, see my page titled “Myeloma and stress”).

So have a piece of chocolate today, naaah, make that two!, and don’t forget to laugh. 

Life may not be the party we hoped for, but while we’re here we should dance.” (Unknown)

Experimental brain transplants

My sister sent this to me…and I just had to share…

Relatives gathered in the waiting room of a hospital, where a family member lay gravely ill.

The doctor finally came in, looking tired and somber. “I’m afraid I’m the bearer of bad news,” he said, surveying the worried faces. “The only hope left for your loved one at this time is a brain transplant. It’s an experimental procedure…very risky, but it is the only hope. Insurance will cover the procedure, but you will have to pay for the brain yourselves.”

The family members sat in silence, absorbing the news.OrganFlyIntoAir[1] After a few minutes, someone asked, “Well, how much does a brain cost?”

The doctor quickly responded, “$5,000 for a male brain, and $200 for a female brain.”

The moment turned awkward. Avoiding eye contact with the women, the men in the room tried not to smile, but a few couldn’t help but smirk. Finally, one of the guys blurted out the question everyone wanted to ask, “Why is the male brain so much more?”

The doctor smiled at their childish innocence and explained, “It’s just standard pricing procedure. We have to mark down the price of the female brains, because they’ve actually been used.”

Curcumin and the H1N1 flu virus: the full study

This is a continuation of my November 7 2009 post on *the first report demonstrating that curcumin exerts anti-influenza activity*. Before jumping into the full study, let’s have a quick look at a couple of items mentioned in the abstract (see: http://tinyurl.com/ybug9sl). The first is one that I had never seen (or paid attention to) before: haema-something-or-other, uhm…let’s see…ah yes, haemagglutination, or hemagglutination with the U.S. spelling. The linguist in me tried to figure out the etymology of this term, but that led me nowhere: the gluing of blood? Blood glue? I finally had to look it up. It means: the clumping of red blood cells (voilà!) caused by viruses, antibodies or other substances. And, according to this study, curcumin inhibits the hemawhatever process. My first question was: is that a good thing? Let me see…yes indeedie, it is. See, e.g.: http://tinyurl.com/q2zys9 and http://tinyurl.com/yfdab7j

The second item is amantadine, which is an antiviral drug administered in cases of oseltamivir-resistant H1N1 flu (oseltamivir is better known as Tamiflu). Amantadine was used in this study as a control for the drug resistance test. Two important findings: 1. in contrast to amantadine, viruses did not develop resistance to curcumin; 2. like amantadine, curcumin inhibited influenza virus plaque formation. Okay, now for the full study.

After giving us the usual overview of curcumin’s multifaceted effects, the authors tell us that Recently, several reports demonstrated that NF-kB inhibitors efficiently blocked propagation of influenza, suggesting that modulation of NF-kB signalling may be a target for anti-influenza intervention. Aha! Inhibition of our old archenemy, NF-kappaB…well, that happens to be right up curcumin’s alley. In fact, that is why curcumin was tested in this study in the first place. And, come to think of it, wouldn’t it follow that any old NF-kappa B inhibitor would block the H1N1 virus? If so, then we would be able to choose from a wide array of natural extracts…not just curcumin but also resveratrol and green tea, just to mention a couple…

At any rate, the researchers administered various doses of curcumin (dissolved in DMSO) at three different times: 1. before infection, 2. together with the virus, and 3. after the virus had been added to the cells. They found that the production of virus was significantly reduced upon treatment with curcumin in a dose-dependent manner; in the presence of 30 micromoles of curcumin, the titre of virus was less than 5% of that in mock-treated cells at all time points of infection analysed.

Based on their tests (I will spare you all the details!), the authors postulate that curcumin may directly interfere with a very early stage (possibly directly with the virus particle), to prevent infection. Curcumin was also found to be effective against avian flu (=H6N1).

Let’s go back to the abstract for a second. It ends with a rather puzzling sentence: the methoxyl groups of curcumin do not play a significant role in the haemagglutinin interaction. The full study sheds some light on this issue (skip this paragraph unless you are fascinated by methoxyl groups…): Commercially available curcumin consists of three major components: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. The structure of curcuminoids differs only by the number of methoxyl groups. So one of the study aims was to determine what part these methoxyl groups played in the Flu Virus Battle. Apparently none whatsoever, since all three curcuminoids were effective against the virus, regardless of methoxyl group content. (Yep, I am yawning, too!)

An issue of huge importance is viral resistance. Flu variants resistant to oseltamivir/zanamivir as well as to amantadine and rimantadine have already popped up all over the world. The researchers compared amantadine and curcumin and found that resistant strains developed to amantadine but not to curcumin, indicating treatment of curcumin is not prone to emerging of resistant viruses. Good to know.

Many blog readers have asked me about dosage. Ah, this is where things get a bit muddled (for me, at any rate). Since the abstract is available online, let’s look at this excerpt: treatment with 30 micromoles of curcumin reduced the yield of virus by 180px-Close-up_of_mole[1]over 90% in cell culture. Okay, let’s take a deep breath…micromoles. No, these are not teeny tiny moles (right photo) digging teeny tiny holes in our gardens and no, they are not even itsy bitsy marilyn monroe[1]beauty marks (left photo). Okay then, if you really must know, in scientific measurements, a micromole is a concentration of one one-millionth of a mole per liter. Ah yes, this is soooo helpful (not!!!).

Well, I have never hidden the fact that math has never been my forte. I looked at conversion charts and molecular weights and filled page after page with divisions and multiplications until I became quite giddy. I gave up.

My blog reader Rebecca has already tried to answer the question for me: her naturopath told her that it would be impossible for us to reach the concentrations used in this cell study. Well, that is certainly, uhm, encouraging…

But hey, all is not lost, in my opinion. As I have mentioned in previous posts (and this is confirmed by private exchanges I have had with Prof. Aggarwal), curcumin works at different levels inside the body. Not just in the bloodstream. And in fact, ever since I began taking curcumin I have been much healthier, as strange as that may sound. It could be a mere question of mind over matter, but I doubt it. Something is definitely happening…

In conclusion, I figure that curcumin, in association with a healthy diet, exercise and a huge dose of caution–avoiding crowded places, washing our hands frequently, etc.–will lend a hand, if only a micromole-sized hand!, in protecting us during this flu-ridden period (I just heard that 1.5 million Italians have contracted the influenza A, or H1N1…yikes!). I have to believe that…otherwise, reading, doing research for, writing and posting about this study has been a complete waste of my/our time…sigh!

A case of spontaneous remission in smoldering myeloma

A blog reader (thank you!) sent me a remarkable study published in the “Journal of Clinical Oncology” (JCO) in October 2009. Unfortunately, there is no abstract (you won’t need it, though, since I will give you a summary of the study…uhm, just don’t tell anyone…shhh!). The title says it all: “Spontaneous Remission in a Patient With t(4;14) Translocation Multiple Myeloma.” Spontaneous REMISSION? Wow.

I had to look up the meaning of “t(4;14) translocation.” A 2007 study (see: http://tinyurl.com/ylqjves) informed me that patients with this translocation apparently have “reduced survival” and their myeloma is characterized by drug resistance and rapid relapse. It does not respond well to conventional chemotherapy. (More details are available in the full study, available for free online at the link provided.)

Okay, now back to the JCO study. In December 2005, a 60-year-old woman with high ESR (121 mm/h!) and low Hb (113 g/L) was diagnosed with asymptomatic, or smoldering, myeloma. More precisely: Durie-Salmon stage 1A/International Staging System stage I multiple myeloma.

At that time, her IgA (kappa) was 30,3 g/L, her bone marrow had 20-30% of the evil cells, and skeletal x-rays revealed osteopenia (that means lower than normal bone density) and “multiple subtle lucencies.” Her creatinine was slightly elevated, but the rest of her markers, unless I missed something, fell into the normal range. I noticed that her B2M was right on the high end of normal, though. And then, of course, there was this business of the above-mentioned t(4,14) translocation.

I was puzzled by her SMM diagnosis, actually, given the t(4,14) translocation and the “subtle lucencies.” That doesn’t sound like asymptomatic myeloma to me, but of course I am not an MD. Well, let’s go on.

There follows a series of technical terms that I do not fully comprehend…just to give you an example: tests revealed the presence of a hyperdiploid karyotype with trisomies of chromosomes 3, 4, 9, 18, and 19, and monosomy 13, as well as a focal deletion on chromosome X containing […] three genes that have been implicated in the pathogenesis of cancer. I don’t have the time to look up this stuff right now, so I will simply have to ignore it.

She was treated only with monthly intravenous infusions of pamidronate. Incredibly, her M-protein began declining. In December 2005, her IgA was 30,3 g/L; in June 2006 it had decreased to 2,23 (!). At that time no paraprotein could be detected by immunofixation. A BMB revealed the presence of a mere 5% neoplastic cells, and her blood tests, freelite included, were all normal. Her skeletal survey remains unchanged.

More details (doing a bit of copy and paste here, to make things clearer). The authors inform us that their patient was also diagnosed with type I cryoglobulinemia IgA-kappa. Cryoglobulinemia refers to the presence of immunoglobulins in serum that precipitate at cold temperatures. In fact, one of my dearest blog readers has this type of problem. In winter he has to stay mostly indoors.

Her type I cryoglobulinemia IgA-kappa was diagnosed in 1985 when she presented with arthritis, purpura, and Raynaud’s phenomenon. Cryocrit had ranged from 0%to 25% over the years and most recently was 5%. She did not require treatment until 1989, when she was placed on low-dose prednisone 5 to 7.5 mg/d.

After almost four years, the woman is still in complete remission. The authors say that they have documented spontaneous remission (SR) in a patient with IgA-kappa MM only receiving pamidronate and intermittent low-dose prednisone. SR of cancer is defined as a complete or partial, temporary or permanent disappearance of all or at least some parameters of a soundly diagnosed malignant disease without any medical treatment or with treatment that is considered inadequate to produce the resulting regression. This is an extremely rare event with a reported incidence of less than one in 60,000 to 100,000 people with cancer.

To the authors’ knowledge, there is only one other documented case of SR in myeloma, a 68-year-old man with multiple lytic lesions and nonsecretory myeloma. His case, briefly: after having surgery on his spine, he developed a a Staphylococcus aureus infection. After 10 cycles of chemotherapy with vincristine, cyclophosphamide, melphalan, and prednisone/vincristine, carmustine, doxorubicin, and prednisone, García-Rayo et al documented complete radiological resolution of the bone lesions precipitating the diagnosis and absence of plasma cells in a repeat bone marrow biopsy. This was interpreted as a case of SR in the context of infection. Infection…interesting, huh?

The researchers point out that nitrogen-containing bisphosphonates can have antitumor effect in human myeloma cells in vitro. But the results from murine models have been contradictory. Based on the literature, there seem to be only four cases suggesting antimyeloma effects of bisphosphonates, specifically pamidronate.

The study concludes: Recently, it has been discovered that nitrogen-containing bisphosphonates such as pamidronate can stimulate human gamma delta T-cells, both in vivo and in vitro. We speculate that the cytolytic activity against MM cells exerted by gamma delta T-cells stimulated by pamidronate could be one of the mechanisms responsible for the SR of our patient, as we were not able to demonstrate direct antitumor activity of pamidronate against cells lines or primary patient samples in vitro (results not shown).

What to conclude from this? The authors don’t know for sure, and I certainly am not going to start having pamidronate infusions (=side effects can be really nasty). But I would be curious to know if any readers have derived benefits from pamidronate. Please drop me a line or, better yet, leave a comment here if you have. Thanks!

Okay, listen up, MGUSers and SMMers!

This morning a blog reader (super duper thanks!!!) sent me the link to a paper that will be presented at the upcoming ASH (=American Society of Hematology) annual meeting. See: http://tinyurl.com/ykye8pf

Well, this was a bit of a shocker (in a very good sense!) that made me drop everything I was doing and write this post…

In a nutshell, a Japanese MGUS patient (IgA-kappa) began taking something called hesperetin-7-glucoside, a more bioavailable form of hesperetin, which is a flavanone found in grapefruit and oranges (citrus fruit in general). And the patient’s M-protein decreased from 2,080 to 878 mg/dL over a three-year period. Her/his hematologists took notice, good for them!, and decided to test this compound on MM cells.

They found that Hesperetin showed inhibitory effects in a dose-dependent manner on the growth of 4 myeloma cell lines and freshly isolated myeloma cells. And hesperetin also turns out to be a proteasome inhibitor, just like curcumin and bortezomib (=Velcade). In the experiments, hesperetin annihilated the myeloma cells. Based on these results, an open-label, pilot clinical trial to test the efficacy of hespertin recently began for asymptomatic myeloma patients. Well, please go have a look at the abstract, which isn’t too difficult to read.

Now, this topic definitely deserves more attention, but today I have a bunch of errands to run, so I must put it on hold…like everything else, for that matter!

Oh heck, just quickly…let’s see (I can’t help it, the errands will simply have to wait a sec)…here is an interesting Finnish 2001 study showing the high plasma concentrations of hesperetin (and naringenin): http://tinyurl.com/ybhajrv Brilliant! Well, I will have to make and drink more citrus-based juices from now on, that is for sure.

Speaking of grapefruit, a few words of warning for those doing chemotherapy: avoid drinking grapefruit juice or eating grapefruit without asking your doctor first. Grapefruit contains compounds that block an important enzyme found in the gut and liver. Simply put, this inhibition causes an increase in blood levels of chemo drugs (or of any other substance, for that matter). That is, when chemo patients drink grapefruit juice, drugs that are usually eliminated quickly via that particular enzyme are able to remain in the bloodstream for longer than warranted. Obviously not a good thing. The reverse is true in the case of poorly bioavailable substances, such as curcumin. Drinking grapefruit juice with curcumin probably helps us absorb it better. 

At any rate, those of us who aren’t on chemo AND aren’t allergic to citrus fruit have absolutely nothing to fear. So, go ahead and drink up! Yum yum.

P.S. For more information on flavanones: http://tinyurl.com/ybsge86 (Here you will also find a helpful chart that distinguishes between flavone, flavonol, flavanone and flavanonol.)