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! 😉