April 12 2008 post. I think hedgehogs are among the most adorable creatures in the world. Under certain circumstances, though, the word “hedgehog” does not have a positive connotation, as we will see in this post. I refer specifically to the hedgehog signalling pathway, or Hh.
If you need to refresh your memory re. Hh, please have a look at my page on cyclopamine. Just quickly, though, as we can read in the abstract, this signaling pathway causes the formation and progression of a variety of tumors. And, in the full study: Besides its crucial roles in development, aberrant Hh/GLI signaling in adult tissues has recently been implicated in cancer formation and development, in the skin, brain, prostate, upper gastrointestinal tract, pancreas and lung.
Is the hedgehog pathway signalling also involved with myeloma? You betcha! Just take a quick look at this study (http://tinyurl.com/3zhw9h), which shows that the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment. Hh and myeloma stem cells are best friends, simply put. But when the researchers used cyclopamine to block Hh, the clonal expansion of the myeloma stem cells was significantly affected. The myeloma stem cells, in other words, were not able to renew themselves. Groovy!
I am writing about this topic today because a Beating-Myeloma list member (thank you!) sent me a note about a recent study on zerumbone, a cytotoxic substance extracted from Zingiber zerumbet Smith, a sort of wild ginger. Sherlock sent me the full study (abstract: http://tinyurl.com/54xpp5).
Once again we come across our friend cyclopamine, the hedgehog antagonist that specifically inhibits Smo, an acronym that stands for Smoothened, a transmembrane protein necessary for the activation of hedgehog target genes. Smo mutations can disrupt the hedgehog pathway and lead to cancer. Obviously, not good!
At any rate, the researchers found that, like cyclopamine, zerumbone, the substance I am interested in right now, antagonizes Hh. One big difference, though. Cyclopamine, as I mentioned, targets Smo, an earlier stage of Hh, whereas zerumbone (and a few of the other compounds examined in this study) affects the final stage of Hh, which is called GLI1 (the acronym stands for “glioma-associated oncogene homolog 1,” aren’t you glad you know that? 
).
The researchers tested 94 compounds from our natural product library, including terpenoids, flavonoids, phenylpropanoids, their glycosides and bisindole alkaloids […] and identified two sesquiterpenes and four bisindole alkaloids as inhibitors of GLI-mediated transcription. So they found six compounds that will inhibit GLI1, including zerumbone.
They also tested another 192 tropical plant extracts (extraordinary, no?), and those that were cytotoxic were again screened at lower concentrations. This part of the text, in fact MOST of the text, was very difficult for me to follow, so I had to skip some parts that were beyond my comprehension. A lot of it had to do with the procedures used in the screening, which we don’t really need to know (if anyone wants to read this very technical part, though, I would be happy to forward the study privately; just leave me a comment here).
The expression of the anti-apoptotic Bcl-2 protein is also involved with hedgehog. But the level of this protein was reduced by some of the compounds under scrutiny. This proves that hedgehog inhibitors also reduce the expression of the antiapoptotic protein Bcl2. This result also supports the reported relation between Hh antagonists and inhibition of Bcl2 expression.
Zerumbone is one of the compounds that suppresses the expression of the antiapoptotic protein Bcl2 and up-regulates the expression of the proapoptotic protein Bax; this results in an increase in the Bax/Bcl2 ratio. […] Our findings suggest that the suppression of Bcl2 expression might be due to the inhibition of GLI-mediated transcription. Inhibit the hedgehog signalling pathway, in other words, and Bcl-2, one of the bad guys, is also affected. Two birds with one stone. Sounds good to me!The researchers examined a human pancreatic cancer cell line (PANC1), which expresses numerous Hh/GLI signaling pathway components. They found that the compounds inhibit the expression of these components at the transcriptional level. Take my word for it, this is important. And since, as I have mentioned, other natural extracts were tested in addition to zerumbone, I have a lot of work ahead of me.
One last bit of intriguing news, though: zerumbone also inhibits the Epstein-Barr virus…see: http://tinyurl.com/4lbh92
May 12 2008 post. Before we left on our Northumberland holiday, a laughing friend (thanks!) sent me a 2005 MD Anderson study on zerumbone published in “Oncogene” and co-authored by Prof. Aggarwal (is there a natural substance that this remarkable man has NOT tested???). The abstract can be viewed here: http://tinyurl.com/3rzdpa
I had already read elsewhere that zerumbone suppresses the activation of constitutive NF-kappaB ("constitutive" essentially means “active all the time,” which is a BAD thing, see my page on Nuclear Factor-kappaB for details), thus preventing a lot of nasty things from happening. The abstract tells us that it also suppresses, just to give a few better known (to me, anyway) examples, COX-2, Bcl-2 and the Epstein-Barr virus, AND it potentiates the killing effect of chemotherapy on cancer cells. So far, so good.
The full study begins with Hippocrates’ famous “Let food be thy medicine and medicine be thy food.” The study then provides a quick account of zerumbone that was first isolated in 1956 from the essential oil of rhizomes of a wild ginger, Zingiber zerumbet Smith, which is widespread in Southeast Asia.
Only about 40 years later, beginning in the 1990s, did it get the attention it deserved, though, as the following excerpts prove: zerumbone has been found to suppress the proliferation of colon cancer and breast cancer, with minimal effects on normal cells. Zerumbone has also been shown to suppress inflammation, suppress the initiation and promotion of skin tumors in mice, etc. Boy, this could easily turn into a sort of cancer “laundry list”! Ok, let me read on and do my best to avoid any mentions of laundry (of which I have been doing tons since we got home from our wonderful holiday…!).
Let’s see. On the one hand, zerumbone is a very potent inhibitor of TNF-induced NF-kB activation. TNF stands for tumour necrosis factor, by the way (hmmm, this is a rather complicated topic that I may address at some point, but for now let it suffice that in this particular scenario, that is, by activating NF-kB, TNF behaves badly, a bit like Mr. Hyde). Anyway, this plant extract suppresses TNF-induced invasion activity, which means it can block tumour metastasis…in vitro at least. I also found it interesting that cells pretreated with zerumbone showed no activation of NF-kB, even after 60 min of TNF stimulation. No activation of NF-kappaB. Extraordinary, no?
On the other hand, zerumbone increased the killing effect of TNF (this time, in its Dr. Jekyll role) on cancer cells by blocking NF-kB. See, I told you it was complicated! Okay, forget this entire part…for now, at least! I will jump to the Discussion section of the study.
The purpose of the study was to see if the antiinflammatory and antiproliferative effects of zerumbone were mediated through modulation of NF-kB and NF-kB regulated gene products involved in inflammation, proliferation, and apoptosis. The researchers found that zerumbone suppressed NF-kB activation induced by various carcinogens and inflammatory agents irrespective of cell type. Super duper.
There are heaps of details in this study, and I confess that I avoided listing them here as much as possible since they were of as much interest to me as a report on the newest most fashionable hair style/colour (yawn!), and I very much doubt they would have grabbed the attention of more than a few of you. However, I would be glad to forward the full study to those of you who enjoy reading about hetarodimers, IkappaBalpha phosphorylation (also suppressed by zerumbone, by the way) and annexing V staining…
Well, okay, here are a few details for the detail-hungry readers: in addition to inhibiting NF-kB (etc.), zerumbone downregulated NF-kB dependent gene products involved in cell proliferation (e.g. cyclin D1 and c-Myc), in antiapoptosis (e.g. survivin, IAP1, IAP2, XIAP, Bcl-2, Bcl-xL, Bfl-1/A1, and FLIP), and in invasion (MMP-9, COX-2, and ICAM-1). Now, aren’t you GLAD I spared you most of the details? 
I was interested to see that zerumbone also inhibits MMP-9 (so does thalidomide, by the way, if I am not mistaken), or matrix metallopeptidase 9. I have written on previous occasions about this human enzyme that of course is involved, and not at all in a positive way!, in myeloma (see for instance: http://tinyurl.com/3w54k8) and angiogenesis.
The study concludes: On the basis of our findings, we conclude that zerumbone is a potent inhibitor of NF-kB and NF-kB-regulated gene products and that this inhibition may explain its antiproliferative and antiinflammatory effects.
Here we have another substance that shows tremendous potential in the lab…but, okay, it’s a bit early to get overly excited, since zerumbone is not easy to obtain, and besides, it also would appear to cost an arm and a leg (I received an actual quote from a lab…mamma mia, quanto costa!!!). Drat!
So, given these obstacles, you may rightly ask me: what’s the point of researching and writing about any of these substances that have strong anticancer effects in vitro but are not being tested outside a lab setting?
Well, my main purpose is to get the word out via my blog.
You see, I believe that we can do something to change the current situation, in which promising anticancer plant extracts are essentially being ignored (for obvious reasons, just think of “Sicko”…).
One small and easy thing that we can all do is take the studies about zerumbone (or a substance of your choice, just take your pick among my Pages, e.g.) to our doctors and try to spark their curiosity.
Here, I hope, is an encouraging example. Out of curiosity this morning I did a search for “curcumin and cancer" on PubMed, where I found a total of 806 studies. Now, what follows may not be very scientific, but it does show how the interest in curcumin has been rising throughout the years.
In 2001 there were 41 studies on curcumin and cancer. Last year there were 129. And right now, that is, just a few months into 2008, there are already 48 studies. Astonishing, no?
The irrepressible optimist in me is convinced that we (cancer patients and/or curcumin-takers in general) have a lot to do with this change.
So if we can get just one doctor interested in zerumbone or cyclopamine or DMAPT or another plant extract…even just one doctor…