December 4th 2007 post. The September 2007 issue of Molecular Cancer Research has a fascinating study, co-authored by Prof. Aggarwal, titled: Ursolic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells. The abstract can be viewed here: http://tinyurl.com/2fkrxl As usual, thanks to my friends, I have read the full study. Ursolic acid can be found in rosemary, apples, bilberries, cranberries, pears, peppermint, lavender, oregano, holy basil, thyme and prunes. There are a ton of studies on the anti-cancer effects of this plant extract, but today I want to focus on this one in particular.

First, a word or two on STAT3. According to one of the main studies on myeloma and curcumin, published in 2003 in the Journal of Immunology (full text: http://tinyurl.com/397tow), STAT3, which stands for Signal Transducer and Activator of Transcription 3, is a cell signalling protein and a prime anticancer target because it can protect cancer cells from apoptosis. Curcumin inhibits the activation of STAT3, quelle surprise. Another inhibitor of STAT3 is capsaicin (see my capsaicin Page on the right): Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor.

The ursolic acid study tells us that STAT family proteins have been shown to play an important role in tumor cell survival and proliferation, and in particular STAT3 is often constitutively active in many human cancer cells including multiple myeloma, leukemia, lymphoma, and solid tumors. It can be activated by IL-6 (interleukin-6), by the way. Without going into too much detail, what we want to do, clearly, is inhibit STAT3. One way is through DIET, that is, eating foods that contain ursolic acid. So much for my being told, back in 2005, that there was nothing I could do to stop the obvious (by then) progression from MGUS to MM. Drat. I wish I had known back then a fraction of what I know now. But, as the saying goes, better late than never/meglio tardi che mai!

The study tells us that Ursolic acid is a pentacyclic triterpenoid that has been shown to suppress the growth of various hematopoietic tumors, inhibit tumor promotion, and inhibit tumor angiogenesis. We have recently shown that ursolic acid is a potent inhibitor of nuclear factor-kB (NF-kB) activation pathway, which is activated by inflammatory agents, carcinogens, and tumor promoters. In this study, the researchers wanted to test their theory that ursolic acid suppresses the STAT3 pathway in myeloma cells. They were successful.

The following will be of interest in particular to those taking Velcade and Thalidomide: In our experiments, ursolic acid indeed suppressed both constitutive and inducible STAT3 activation. This inhibition decreased cell survival and down-regulated expression of proliferative and angiogenic gene products, leading to suppression of proliferation, induction of apoptosis, and enhancement ofthe response to the cytotoxic effects of thalidomide (an inhibitor of tumor necrosis factor expression) and bortezomib (a proteasome inhibitor; also called PS341) in multiple myeloma cells. Further on, we read that ursolic acid significantly enhanced the apoptotic effects of thalidomide from 20% to 70% and of bortezomib from 25% to 80%. Now, those are significant numbers, I’d say!

I cannot examine every single bit of information provided by the study, but for instance ursolic acid increased the expression of Bax and Bak proteins, which cause apoptosis in myeloma cells. Yeah! Also, similarly to capsaicin, ursolic acid suppresses the expression of several STAT3-regulated genes, including proliferative (cyclin D1) and antiapoptotic gene products (survivin, Bcl-2, Bcl-xL, and Mcl-1) and angiogenic gene product (VEGF). Super. At the end of the study we find a reference also to other cancers, including head and neck cancers, hepatocellular carcinoma, lymphomas, and leukemia. They, too, also have constitutively active STAT3. The suppression of constitutively active STAT3 in multiple myeloma cells raises the possibility that this novel STAT3 inhibitor might also inhibit constitutively activated STAT3 in other types of cancer cells.

This is excellent news. Stefano and I grow quite a variety of herbs in our garden, including at least four or five different types of thyme and two of rosemary. We even have an oregano plant. Herbs add taste to any dish, as we know but using herbs in our cooking goes way beyond taste enhancement, now that we have discovered that ursolic acid inhibits a crucial myeloma survival pathway, inhibits the proliferation of myeloma cells AND induces apoptosis in the same why, I believe it’s time for a little dance of joy !