October 1 2009 post. 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.
Second part, October 2 2009:
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.