October 8 2007 post. Yesterday morning, by chance, while looking up the most recent news on parthenolide online (nothing new to report since my October 3 post, by the way), I came across an interesting website, Cancer Research UK (http://tinyurl.com/2xh2wc). Its list of articles included one with my blog title, i.e., Modified Cold Virus May Kill Cancer Cells. Hmmm, intriguing title, I thought, so I clicked on the link and read that researchers from Birmingham University have developed a genetically modified form of the cold virus, a form that will not replicate (i.e., it won’t make us cough or sneeze) but merely serves as a vehicle to transport a human protein called CD40L to a cancer cell. Here it sticks to another protein, called CD40, which is present on the surface of many types of cancer cells (breast, liver and skin cancer, to mention a few). And the result of this sticky business? Apoptosis!
I could have stopped at that, but no, I just had to see if CD40 is present on the surface of myeloma cells. It is. So I dug deeper. Mamma mia! What a headache. I admit that I find myself more than a bit overwhelmed after being fully immersed in molecular science research for the past 36+ hours. So many studies, so much virtually incomprehensible technical lingo, so little time (and desire!) to earn a degree in biology and chemistry! I have now come to doubt that this cold vehicle could be useful to myeloma patients (see below). In fact, this morning I almost threw away all my research and writing, but, to be honest, the CD40 topic was interesting, and the targeting of this protein may be relevant in the near future conventional treatment of myeloma, so I edited out some of the more convoluted stuff and decided to give the topic a quick whirl. CD40 is an interesting molecule. It is present, at low levels, also on the surface of healthy cells, for instance of B cells (immune system cells). Under normal circumstances, I read, it is supposed to defend us from the attacks of viruses, bacteria and harmful substances and can even provoke apoptosis in tumour cells. However, it does not always perform as well as it should, which can be a big problem. In order to become activated, it needs to bind with its ligand, which I found also endearingly described as its soulmate, i.e., the above-mentioned CD40L ( L stands for ligand, by the way), also known as CD154. So, as I understand it, the modified cold virus acts like a little Cupid reuniting two passionate lovers that are lethal to certain types of cancer cells. The embrace between CD40 and its ligand, in fact, sets off a cascade of events that eventually lead to the death of these particular malignant cells.
I should note that a body’s immune system becomes activated during this process. Now, a blog reader recently brought up the point that the immune systems of myeloma patients are already over-stimulated and should not be stimulated any further. I have read warnings to that effect here and there on Internet but have to confess that it is not a theme that I have researched thoroughly. I recognize that it is an important topic, though, so it will be added on my to-be-researched-in-a-hurry list.
CD40 and myeloma studies. There are heaps of ’em. I will discuss only a few of all the studies I have gone through since yesterday. A 2002 Dana Farber study published in Blood (see full text: http://tinyurl.com/249aog) tells us that CD40 induces MM cell migration and vascular endothelial growth factor (VEGF) secretion, suggesting a functional role of CD40 activation in MM homing and angiogenesis. This functional role is bad news for us, of course. When CD40 is activated, the researchers suggest, the result is tumour progression. CD40 also activates the infamous NF-kappaB, which, as we know, protects myeloma cells from death, via different mechanisms. In essence, CD40 appears to be involved in the proliferation of myeloma cells, so the authors suggest that targeting this pathway may prevent multiple myeloma from progressing. Interesting. This had already been suggested back in 1995, again by a Dana Farber team (http://tinyurl.com/3b983v). Here are a few relevant excerpts from the 1995 Blood study: MM cells can be triggered via CD40L to secrete IL-6, suggesting the possibility for induction of IL-6-mediated autocrine MM cell growth. [ ] CD40L-CD40 interactions between MM cells, or between MM and BMSCs may be implicated in triggering IL-6 secretion and result in both paracrine and autocrine IL-6-mediated tumor cell proliferation. This study stopped me from looking fondly upon the modified cold virus theory. I am not sure what these interactions are, but perhaps it is not a good idea to put these two proteins together in the case of myeloma, unless I have totally missed the point or unless things have changed in the past 12 years, which is more than possible. The study ends: Further elucidation of the in vivo role of CD40-CD40L interactions between MM cells and cells within the marrow microenvironment may, not only elucidate the mechanisms of IL-6-mediated tumor cell growth, but also offer innovative therapeutic strategies. Indeed! The jury is still out. Targeting CD40. Another Dana Farber study (full study: http://tinyurl.com/2fa4t5) published in 2005 discusses an anti-CD40 monoclonal antibody tested against multiple myeloma cells. This antibody, CHIR-12.12, apparently can inhibit multiple myeloma cell growth in the bone marrow milieu. I don’t need to underline the importance of THAT sentence! Two Phase I clinical trials are currently investigating the anti-CD40 theory in multiple myeloma. One is testing an anti-CD40 monoclonal antibody called SGN-40 (Anti-huCD40 mAb) on refractory or recurrent multiple myeloma (see: http://tinyurl.com/ysahre), in various medical centres throughout the U.S. This 2005 abstract provides information about SGN-40 and the above-mentioned trial: http://tinyurl.com/2wd567. SGN-40 apparently inhibits malignant cell growth by both antibody-induced cell death (AICD) and antibody-dependent cell-mediated cytotoxicity (ADCC). The other trial (http://tinyurl.com/2easoj) is testing HCD122, another anti-CD40 monoclonal antibody, on relapsed or non-respondent myeloma patients.
Speaking of clinical trials, the Birmingham researchers are in the process of developing skin and liver cancer clinical trials to test the above-discussed modified cold virus technique. I admit that I find all of these studies interesting, even though molecular science and fiddling around with genes is not my cup of chocolate and curcumin , and I doubt I would ever participate in an anti-CD40 myeloma clinical trial. But hey, the thought that curcumin or one of the other non toxic substances in my protocol might already target this protein just popped into my head. More research tomorrow.
Update, October 12 2007 post: Well, this CD40 project (see my October 8th post) is going to be time-consuming and involved, and I am not even sure how much headway I will make with it, as I am a linguist by trade, not a molecular scientist (sigh). Well, we will see. For now, I did discover that CD40 is inhibited by a few natural substances, and perhaps by many more that have not yet been tested in that sense, "including parthenolide (PTL) and honokiol (HNK). Today I will focus on these two substances. Honokiol, by the way, in addition to downregulating CD40, was found to decrease IL-6 levels, a phenomenon that I had already discussed in my May 12th post on honokiol and multiple myeloma. For more information on these two substances and myeloma, please scroll down my Alternative Research Pages (right-hand of your screen). I would like to mention that I was able to consult the full version of the following (two) parthenolide and honokiol studies thanks to a dear friend (grazie, Sherlock!).
The first study (see abstract: http://tinyurl.com/27ag9l), published in 2002 in the Journal of Allergy and Clinical Immunology, examines the effect of parthenolide on dendritic cells (or DCs), which are immune system surveillance cells that originate in the bone marrow and control the functions of B and T lymphocytes. I looked up dendritic cells and myeloma and found that, according to an Italian study published in Blood in 2002 (see: http://tinyurl.com/22f9cp) , these cells are functionally defective or impaired in myeloma patients (trust me to be the bearer of good news, huh? Well, I wasn’t too thrilled by this discovery, either ). The Italian study also reports that IL-6 has an immunosuppressive role in cancer patients by inhibiting the development of DCs. The latter statement is off-topic (nothing to do with parthenolide, in other words) but worth mentioning, in my view, because the authors soon thereafter suggest that the IL-6 inhibition of dendritic cells may be the mechanism whereby myeloma cells escape recognition by our immune system. Food for (future) thought.
Back to the 2002 parthenolide study. It is very technical, which made it very hard for me to follow. At any rate, as the abstract anticipates, parthenolide was found to downregulate the co-stimulatory molecule CD40 in a concentration-dependent manner, which is important news for us. I am beginning to think that even though parthenolide is another blood-thinner like curcumin, it might be worth my while to give it a try. I intend to ask my haematologist if she has access to DMAPT (see my October 3rd post). The second study deals with honokiol (see abstract: http://tinyurl.com/yqoyn6) and was published in The Journal of Immunology in 2007. It examines inflammatory conditions such as rheumatoid arthritis (RA) but contains information that could be relevant to myeloma and perhaps other cancer patients as well. Here are a few of the more relevant and understandable (!) excerpts: A number of conditions are associated with the chronic inflammation and elevated levels of TNF-alpha and IL-6 seen in RA, including heart disease and cancer. Although the gastrointestinal tract is one of the most common sites of such cancer induction, a similar mechanism can also been found in plasma cells, leading to lymphoproliferative changes, lymphomas, and myelomas. [TNF-alpha is a growth factor for myeloma, as is IL-6.] This statement offers nothing new to those of us who were already aware of the inflammation-cancer connection. The study goes on to explain, however, that CD40, a member of the TNFR superfamily, is a key costimulatory molecule in T-B cell interactions, promoting the up-regulation of inflammatory cytokines such as TNF-alpha and IL-6 and autoantibody production. [TNFR stands for tumor necrosis factor receptor.] Now, I don’t recall ever having read that CD40 can activate IL-6. Interesting. And definitely here we have another strike against CD40.
Treatment with honokiol inhibited the activation of both of these myeloma growth factors, i.e., TNF-alpha and IL-6. This sentence deserved its own separate paragraph!
In the study’s Discussion part, we can read that CD40-mediated B cell activation, a key component of CIA pathogenesis, was inhibited by HNK treatment, and TNF-alpha and IL-6 were diminished in a dose-dependent manner, without decreasing IL-4 or IL-10 secretion. The support of IL-4 and IL-10 production by HNK is particularly beneficial given the established anti-inflammatory effects of these two cytokines. [CIA stands for collagen-induced arthritis.] I looked up these two cytokines, which is one big reason why this post took forever to write!, and, of the two, IL-10 apparently promotes the proliferation of myeloma cells. So the fact that it is not inhibited by honokiol doesn’t seem to be such a good thing. [I should note that high levels of IL-10 are, however, beneficial in other types of cancer, e.g. breast cancer.] And indeed, if we take another look at the above-mentioned Italian study, we find that IL-10 is produced by myeloma cells and could possibily inhibit the differentiation and function of dendritic cells. But perhaps this negative factor for myeloma is offset by the other beneficial effects of honokiol, such as its ability to inhibit NF-kappaB: It is consistent with the anti-inflammatory effect of HNK on CIA to see the dose-dependent inhibition of the transcriptional activators NF-kB and AP-1 in B cells.
The researchers add that they saw an increase in the amount of IgM after treatment with honokiol, which may have resulted from the above-mentioned NF-kB and AP-1 inhibition. We already know about NF-kappaB, but I would like to point out that AP-1 is also an evil transcription factor. At any rate, since honokiol increases the levels of IgM, let’s have a quick look at this immunoglobulin: it is found on the surface of B cells and gets released into the bloodstream during the body’s initial response to infection. Hmmm, perhaps if my IgM levels had been higher than they are at present, I wouldn’t have succumbed recently to that stupid germ. Bring on the honokiol! There is much more information, but I think this post is overwhelming enough so I will stop here. I am also looking at a couple of other natural substance studies in connection with CD40 but don’t yet know if they will be relevant. Okay, I need a nap now. Just kidding!