IGF-1, the American mayapple, curcumin and multiple myeloma. Part II

October 2, 2009 / / 2 Comments

First, I searched PubMed to see if curcumin possibly inhibits this growth hormone that has such a negative impact on myeloma patients. Hah. Quelle surprise! It does! So curcumin-takers are a step ahead, it would seem. Here are the two main studies:

A 2008 study on colon cancer cells, chemo and curcumin (see: http://tinyurl.com/yajdk5s) found that the superior effects of the combination therapy of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling pathways. We also suggest that inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer. (FOLFOX, btw, is a chemo regimen for patients with colorectal cancer.)
A 2007 breast cancer cell (=MCF-7) study showed that curcumin exhibited a potent ability to blunt IGF-1-stimulated MCF-7 cell growth and reverse the IGF-1-induced apoptosis resistance. See: http://tinyurl.com/ye3jqje

I then checked out some of the other anti-myeloma, non toxic substances discussed on my blog. Bingo, again. Here is just a sampling of what I found:

2009 study on resveratrol and genistein: Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate, see http://tinyurl.com/yesbb5q
2008 study (see: http://tinyurl.com/yea69yn): resveratrol significantly inhibited IGF-1 in breast cancer cells.
The 2008 myeloma-parthenolide study that I posted about on June 4 2008 (see my Page on parthenolide or click here for the full study: http://tinyurl.com/ydousu2) shows that parthenolide, extracted from the feverfew plant, overcame the proliferative effects of cytokines interleukin-6 and insulin-like growth factor I, whereas the adhesion of MM cells to bone marrow stromal cells partially protected MM cells against parthenolide effect. (Blasted adhesion!)
2009, prostate cancer-EGCG study (see: http://tinyurl.com/ydkbgw3). EGCG decreased the levels of IGF-1 (as well as having other beneficial effects). Same thing for colorectal cancer, see http://tinyurl.com/yat8wjt .

This post could easily turn into a long boring laundry list, so I will stop here. However, if you want to find out if any of the supplements that you are taking might inhibit IGF-1, just go to PubMed (general link: http://www.ncbi.nlm.nih.gov/) and type in your key words. Easy peasy.

Let’s move on. I would like now to discuss a Science Daily article that I read in September: http://tinyurl.com/ydxxcgm It gives us an overview of podophyllotoxin, an anticancer compound extracted from the roots and rhizomes of an endangered Indian medicinal plant but also from those of the common American mayapple (for an overview of this plant: http://tinyurl.com/yccs83x). This compound, incidentally, is found in the chemo drug etoposide, used to treat lymphoblastic leukemia, brain tumours and other types of cancer. The abstract of the study discussed in the SD article can be found here: http://tinyurl.com/nh4grx

As usual, I checked PubMed, where I found that picropodophyllin was tested in 2007 against myeloma cells, too. Hah! And, double hah!, the full study is available online: http://tinyurl.com/y8p4nzh The results are astounding: targeting the IGF-1R using picropodophyllin (PPP) in a therapeutical setting not only has strong antitumor activity on the established MM tumor but also influences the BM microenvironment by inhibiting angiogenesis and bone disease, having a profound effect on the survival of the mice. Wowie.

An important point: this study tested the impact of PPP in models of established myeloma, that is, not just on MM cells. They used what is called the 5T2MM mouse model, representing an in vivo model of established, slow growing myeloma. Now, you can read the details on your own (the study isn’t a difficult one compared to others I have encountered!), but let me give you just a few interesting results:

PPP significantly reduced the tumor burden in the 5T2MM model. Up to 75% reduction in serum paraprotein.
PPP reduced the accumulation of myeloma cells in the spleen by 70%.
Mice treated with PPP survived 180 days…compared to the 100 days of the untreated ones.
PPP also inhibits angiogenesis (good news for us).
PPP may have a direct effect on osteoclast formation and osteolysis. It inhibits osteolytic lesions, a colossal problem in myeloma, as we know.
The study concludes that blocking IGF-1R signaling with the receptor inhibitor PPP not only has a strong antitumoral effect in MM but also has a significant impact on the BM microenvironment, a key contributor to MM tumor expansion.

Let me point out that there are a couple of previous studies on the myeloma-picropodophyllin issue: a 2006 study (full text: http://tinyurl.com/yakrvy6) that I haven’t had the time to read yet, but that concludes that PPP targets the IGF-1RTK, blocks the IGF-1R function in vitro and in vivo, reduces tumor burden, and is associated with prolonged survival and this in the absence of apparent in vivo toxicity.

The same edition of “Blood” has a study by the same group of researchers (full text: http://tinyurl.com/ydcqfl8), which comes to the same conclusions. I would like to highlight that PPP also decreased the levels of survivin and mcl-1, among other things.

I have more (strong) thoughts on this topic, but that is fodder for a separate post. Stay tuned!

IGF-1 and multiple myeloma. Part I.

October 1, 2009 / / Leave a comment

This is not an easy topic. Therefore, I am going to divide it into two parts. In the first, I will make a feeble attempt to provide a brief description of IGF-1…focusing mainly on what it means for myeloma patients. In the second part, I will bring up a couple of things that we can do to give it a big whack…

IGF-1 stands for insulin-like growth factor 1. As its name implies, its molecular structure is similar to that of insulin, but its main purpose is not to decrease blood glucose levels but rather to stimulate the growth of normal cells (IGF-1 affects almost every cell in the body, I read)…and also–and here we get to the crux of the matter–the growth and survival of cancer cells.

Why am I interested in this growth hormone? Well, because in May I read a “Blood” abstract (see below), which showed that there is a connection between IGF-1 and myeloma cell proliferation…and this is not a super recent discovery, by the way. If you do a PubMed search, you will find studies on this issue that date back to the 1990s.

For instance, a 2000 French study (full study: http://tinyurl.com/ybwyngc) tells us that an important mediator of bone remodelling, IGF-1, has been shown to stimulate the proliferation of human myeloma cells. The researchers add that the mechanism involved is still a mystery…but after all, understanding the intricate workings of this process does not matter one whit to me…heck, I probably wouldn’t understand it anyway!

What matters to me is that there is a connection between IGF-1 and myeloma cell proliferation and survival, as we can read in a more recent (2008) study (abstract: http://tinyurl.com/kmbqcs): IGF-1 and IL-6 promote the proliferation and survival of multiple myeloma cells.

Sherlock (grazie!) sent me the full study, from which I took the following excerpt: the IGF-1 receptor (IGF-1R) is universally expressed on multiple myeloma cells, and higher expression levels are correlated with poorer patient prognosis. Okay, I admit that I merely skimmed the text, in part because I don’t have a huge amount of time, but also because this is an extremely complicated technical study, the splitting-headache kind….I finally had to set it aside and give up, at least for now.

Anyway, if you need more convincing that IGF-1 is bad news for us, here is the abstract to a May 2009 study published in “Blood”: http://tinyurl.com/ydl95ye Of the five myeloma growth factors (or MGFs) examined, IGF-1 was the major one…even worse, if possible!, than our old archenemy, IL-6. And here is a bad bit concerning prognosis: Of the investigated MGFs and their receptors, only expressions of IGF-1R and IL-6R in multiple myeloma cells (MMCs) of patients delineate a group with adverse prognosis. Ouch.

I should note that IGF-1 isn’t all bad. It is essential for normal growth and development (but of course we aren’t kids anymore!)…and I also found a study showing that it had a beneficial effect on cardiomyopathic hamsters: http://tinyurl.com/y99h3yo

Okay, but, in the case of multiple myeloma, high levels of IGF-1 = a bad thing. Clearly.

That’s it for today. More tomorrow, providing I can finish my research for Part II…

Last but not least: sweet little Jaymun, you hang in there! (see Jaymun’s journey)

Viva la ciccia!

September 28, 2009 / / 2 Comments

My parents are leaving for the U.S. later today. I won’t see them again for months, but I don’t want to think about that right now…I want instead to write about what we did yesterday.

Yesterday morning Stefano suggested that we drive down to Panzano, near Greve in Chianti…if that means nothing to you, well, it’s in the heart of Chianti wine territory, roughly halfway between Florence and Siena. Typical Tuscan scenery—olive groves, rolling hills, old farmhouses, ancient turrets, vineyards…lovely, still not too spoiled…

We had lunch at a restaurant managed by Dario Cecchini and his family. Cecchini is “perhaps the most famous butcher in the world,” according to Anthony Bourdain (see: http://tinyurl.com/dgldnv). Certainly the most famous in Italy. His restaurant is called “Solo Ciccia,” which means “Only Meat” in the Tuscan dialect.

It came as a surprise to us that everyone sits together at the same table, just like an extended family. Our “family” consisted of a U.S. couple from Chicago and three Tuscan nuclei—an elderly couple, a young couple, and three women (mother, daughter, aunt). By the time the first platters of food arrived, we were all chatting, in English and Italian. Lovely.

I forgot to take photos of the different types of food we ate, mostly meat-based of course…more than ten platters of mouth-watering food…batter-fried meat and veggies, braised and roasted meat etc., accompanied by a truly outstanding Chianti red wine…oh, and, while we were having olive oil & pine nut cake with grappa and other liqueurs at the end of the meal, the butcher-poet himself made a quick appearance to say hi and make sure that we had eaten enough and were having a good time…a man of huge charisma, that Dario Cecchini!

We spent a total of two hours at the table…the restaurant has a fixed price, and you cannot choose single items from a menu. You have to eat whatever is brought to the table, but I assure you that we ate and ate and ate until we could eat no more. And the woman who served us this incredible amount of food kept accusing us of not being hungry and pushing us to eat more, just like a stereotypical Italian mamma…

If you are travelling to Tuscany…well, this is an experience that I would highly recommend…unless you are a vegetarian, of course!

P.S. My photo depicts two marble signs posted outside Cecchini’s butcher shop. The one on top commemorates the “demise” of the famous Florentine T-bone steak, the thick and delicious “bistecca alla fiorentina,” which occurred in 2001, when certain cuts of meat were banned as a result of the mad cow scare that swept Europe in the late 1990s. I remember news reports showing hundreds of steak lovers attending Panzano’s mock funeral procession for the bistecca. The ban was lifted five years later, a fact that is gleefully celebrated in the second marble plaque (brightened by a real red rose).

(Plaque 1: “ridotta invalida, preferì la morte.” In memoria della bistecca alla fiorentina, scomparsa prematuramente il 31 marzo 2001. Plaque 2: Le mie preghiere alfin furon accolte. Torna la fiorentina e ben ci azzecca. Invalida morì, visse due volte. E infatti il nome suo com’è: bistecca!)

I’m an ailurophile…

September 20, 2009 / / 2 Comments

Day before yesterday a blog reader sent me the full study on curcumin and myeloma cells’ multidrug resistance…yaaay! Then this morning another blog reader did the same, joking that it had actually not yet been translated but was still in the original Chinese (haha…well, yes, I admit, it is not at all an easy text to read…), but I haven’t had the time yet to transla…er, I mean, read it through carefully enough to write a draft. Perhaps tomorrow…

Today I have time only for a quick post before Stefano takes my computer apart (these things always makes me jittery, even though he is a computer genius and always creates backups of backups…of backups). There is something wrong with one of my hard disk drives…no biggie, he can fix it easily. It will just take all afternoon.

So I thought this would be a good day to tell you that I just found out I’m an “ailurophile.” How about that? Hmmm, might you be an ailurophile, too?

Yesterday I saw that Richard Lederer, of “Anguished English” fame, has written two new books, one for dog lovers, one for cat lovers. It is here http://www.verbivore.com/adven.htm that I first clapped my eyes on the word “ailurophile,” which, I now know, means “cat lover” (in ancient Greek, ailouros = “cat”). Hey, try saying “ailurophile” ten times fast! Tee-hee.

The above link has some interesting statistics on cats and dogs in the United States…how many people have dogs and cats, e.g., how much they spend on pet food and so on. I am not that surprised…

Like the two ailurophiles in Richard Lederer’s Introduction, I buy only the best food for my cats. But I don’t buy cat food in a regular supermarket. Nope. I go to a specialty pet store…where by now I am friends with the two ailurophile/cynophile owners.

And yes, I still occasionally waste money on cat toys, even though I am well aware that my kitties are probably going to show complete indifference…and I will be the one chasing after the new toy. When we are away, I coo to my magical, mystical cats over the phone sometimes. And I take more photos of them than of anybody/thing else. The list goes on.

As I have written before, cats also have a positive effect on our health and longevity: Studies show that owning a cat alleviates loneliness, anxiety, and depression; reduces stress, high blood pressure, and heart disease; and adds six months to the average person’s life. Well, even though I have cats for reasons other than my health, it is lovely to know that they are adding months to my life…! Now, if only they could cure cancer…

Australian curcumin-MGUS clinical trial results: full study

September 14, 2009 / / 4 Comments

Just minutes after I had asked her, Sherlock sent me the full study…a blog reader did the same just a few hours later…then another blogging friend…so now I have three copies of the same study…fabulous! Thank you all!

Let’s dive right into the report, which is only six pages long but is packed with interesting information. There is so much good stuff, in fact, that it was difficult not to go ahead and print the whole thing! (I cannot do that, of course, for obvious reasons…)

It begins with a description of MGUS and how it differs from multiple myeloma, including this item of interest, which explains why the bone turnover marker is so important, even in MGUS: Although MGUS is largely considered a benign condition, a number of studies show that patients with MGUS are at increased risk of developing fractures even before progression to myeloma. Elevated bone turnover is an independent predictor of fracture risk, and a number of studies have shown elevated bone resorption and/or reduced bone formation among patients with MGUS and myeloma. Incidentally, in case you have MGUS and were a bit taken aback by the words “even before progression to myeloma,” don’t forget that the overall risk of progression MGUS-MM is a mere 1% per year.

Now read this: It is currently not possible to predict the course in any individual patient, and clinically symptomatic myeloma may not evolve for as long as 20 years. Whoa. I don’t think I have seen a sentence like that in any other study–clinically SYMPTOMATIC myeloma may NOT EVOLVE for…TWENTY years??? I had no idea…

The researchers note that matters are different for those who are in a high-risk group—e.g., with high levels of M-protein or heaps of evil cells in the bone marrow or an abnormal free light chain ratio or IgA and IgM instead of IgG.

Well, let’s get to the part about curcumin. First comes the description of the Curcuma longa plant and the various properties of its active ingredient, curcumin. We know most of this stuff, including the fact that Curcumin has also been shown to inhibit osteoclastogenesis and thus reduce bone turnover. And then we get to one of the reasons underlying this clinical study: Based on the antimyeloma cell activity and inhibition of osteoclastogenesis exhibited by this polyphenol, we postulated that curcumin will inhibit the action of abnormal plasma cells and affect the activity of osteoclast cells in patients with MGUS. This study offered the opportunity to test a possible preventative strategy with little risk.

Study participants: 26 MGUS patients, 16 men and 10 women over the age of 45, with less than 36 g/L serum M-protein (median: 20 g/L), less than 10% neoplastic cells in the bone marrow and no CRAB symptoms or evidence of metabolic bone disorder. They were separated into two groups in this single-blind cross-over pilot study, which means that group A patients were given curcumin at the start of the study and were then crossed over to placebo at the end of 3 mo. Group B patients were given placebo initially and then crossed over to curcumin.

Aha, here is a useful titbit: Patients consumed two tablets twice daily, i.e., 4 grams/d (this dose has been defined as the dose at which plasma levels of curcumin can be measured and pharmacodynamic effects showed in vivo) half an hour before food or 1/2 h after food and were crossed over at 3 mo after initiating therapy. Treatment continued for 6 mo. This leaves me with a question…were there any differences between the half-hour-before-meals group and the half-hour-after-meals group? I found no answer to that in the study.

Let’s keep going. During the study, two patients developed diarrhea and abdominal cramping and withdrew. Ah, but read this: nine out of twenty-six MGUS folks had a VITAMIN D DEFICIENCY. I highlight that little fact, since I have come to believe strongly in the importance of maintaining NORMAL vit D levels. The researchers make no comment about this possibly significant (or not) finding…so my next project is to have a look at the Tables to see what happens to the low-vitamin-D patients when they start taking curcumin…

In the results part of the study, we can read that half of the MGUS folks whose serum M-protein was more than, or equal to, 20 g/L, experienced a 12-30% decrease in their M-protein levels. And when they were switched over to the placebo group, two of them showed a rebound in their serum paraprotein levels. The less than 20 g/L folks instead did not show a response to curcumin, but their serum paraprotein levels remained stable throughout the study period (that might have happened anyway, of course…).

Now for the placebo group: In contrast to a decrease in serum paraprotein seen in patients initiating curcumin therapy, patients receiving placebo showed stable or an increase in their serum paraprotein levels. When they began receiving curcumin, though, two patients showed a decrease in their serum paraprotein (12.5% and 15%, respectively).

Now for some info concerning bone turnover: Although 73% of patients did not show a change in their uNTx levels while taking curcumin or placebo, 27% of patients showed a decrease in their uNTx levels while taking curcumin. uNTx is a bone turnover marker determined by a urinary test. Some patients, therefore, may show a decrease in bone resorption in response to curcumin. Some, not all…

Discussion: The present study shows that oral curcumin (a known inhibitor of tumorigenesis and osteoclastogenesis) is able to decrease paraprotein load and bone resorption in a select group of patients with MGUS. Fifty percent of patients with a paraprotein >20 g/L responded with a 12% to 30% decrease in their paraprotein levels while taking 4 grams/day curcumin orally. The placebo folks had no such decrease in their paraprotein levels.

And then: Similar reductions in paraprotein have been seen with conventional antimyeloma therapies such as melphalan and dexamethasone. This is the first study, however, assessing the potential therapeutic effect of curcumin in MGUS patients.

The finding that only patients with higher serum paraprotein levels responded to curcumin is fascinating to me. The researchers suggest that this group may have an abnormal plasma cell clone that responds differently to curcumin or its metabolites. In vitro studies may help to differentiate a subpopulation of plasma cells that are curcumin responsive.

And here is more snack food for thought: The partial response rate (i.e., 50-75% decrease in paraprotein concentration) was 0% in both arms. In MGUS patients, the chance of a partial response are low because cell division is very slow. Even in smoldering myeloma, responses take much longer with a drug such as thalidomide compared with relapsed myeloma where cells are dividing more quickly. Indeed.

The researchers conclude by stating that this pilot study has prompted them to commence a double-blind, randomized, control trial using higher dosages of curcumin in a larger cohort of MGUS patients with significant paraproteinaemia. Excellent. I am already looking forward to reading the results of the larger study!