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 Well, it’s getting late, and I must get off this computer.
I can tell that this is going to be a long hedgehog weekend! 
Hi Margaret,
Just after I was diagnosed I uncovered some research on another tropical ginger, Galangal, (used in Thai cooking) that appeared to have anti-cancer properties. I ate quite a lot for a while and we still have some in the cupboard. Perhaps I should start again. Galangal is also active against EBV I believe, and it is fairly cheap and easy to obtain. There are 2 types of Galangal, Lesser and Greater, but I can’t remember which is best.
Cheers,
Paul
PS Do people still say “groovy”? 🙂
In fact, in April of 2007, I wrote about Languas Galangal, a member of the ginger family whose extract, called Acetoxychavicol acetate (ACA), kills MM cells in vitro.
See my Ginger Page for more info and links to various studies: http://margaret.healthblogs.org/other-alternative-treatments/ginger/
This new compound, though, zerumbone, appears to inhibit the cloning ability of the cancer stem cells, which is even better! More research is needed, but I would say that this is very promising news indeed.
I actually don’t say “groovy,” but that is the first thing that popped into my head as I was writing that sentence. Go figure. 😉
Margaret
OK so, if I understand you properly:
Galangal gets rid of differentiated MM cells (as does Thalidomide, Velcade, etc.) but not the stem cells;
Zerumbone stops MM stem cells cloning but doesn’t actually get rid of them; whereas
DMAPT and Cyclopamine actually kill the stem cells – which at the end of the day is what we really want.
Does this mean then that Zerumbone will only keep you stable whereas Cyclopamine and DMAPT are potential cures?
Paul
Good question, Paul. Ok, here are my thoughts, which could well be wrong, eh! Cyclopamine and zerumbone both inhibit the hedgehog signalling pathway, but at two different stages. Since zerumbone targets the final step in this process, though, it would actually seem (to me!) to be more effective than cyclopamine. Once the MM stem cell has gone beyond the SMO stage, in fact, cyclopamine won’t affect it, which we can see in this quote from the March 2007 J. Hopkins study: “NCI-H929 cells transiently overexpressing GLI1 were resistant to the inhibitory effects of cyclopamine on clonal growth.” At the final step, GLI1, cyclopamine is useless. But zerumbone is not: it affects the MM stem cells (NCI-H929 is a MM stem cell population, by the way) right before the cloning-ability stage.
Our main goal is to stop the MM stem cell from duplicating itself, and that can be achieved with both these substances. Eventually, the evil stem cell, like any other cell, will die. But this way, either with cyclopamine or DMAPT or zerumbone or (?), we have taken away its chance to create duplicates! The MM stem cell population is thus doomed.
I think the only way to see what zerumbone will do for us is to give it a try. But first I want to do some more research. There are so many studies to read on zerumbone…mind-boggling!
Margaret
I might have got it wrong but thought the whole thing about cancer stem cells was that they didn’t die naturally. I seem to remember reading about tolymerase??? inhibition. Anyway, whatever the word is, it relates to the bit at the end of the DNA string that normally gets snipped off every time the cell divides.
Paul
Hi all,
Let me try to clear somethings up about the Hedgehog pathway. I have a few papers published on the pathway and read just about every paper that has come out on the Hh pathway. Margaret is correct in theory targeting Gli1 & Gli2 via zerumbone is the best way to target the Hedgehog pathway.
Cancer biology of the Hh pathway.
http://www.pathway2curis.com/Hedgehog%20Pathway%20and%20Metastasis.html
http://www.pathway2curis.com/Hedgehog%20Pathway%20and%20Tumor%20Regulation.html
Basically the Hh pathway is a master regulator of a lot of cancer pathways. Here is another way to think about it, Adult Stem Cells (ASC) and cancer stem cells have a lot of similar properties. I can go into details if you would like.
Currently a Hh inhibitor is in phase II clinical trials for 3 different cancers.
I have nice friend who is getting me a quote for zerumbone purification but I’m not sure what the demand would be? I have already contacted a few hedgehog researchers but I’m more interested in helping somebody with a natural compound.
drew007martin@gmail.com
I am always trying to find out how these drugs get their names, mainly as a way to remember them. Is Cyclopamine named after the Cyclops in the Odyssey which would have a connection to the poor little lambs who were born with only one eye after eating this lily plant? Such a name would relate it to the powerful one eyed giant and its provenance with those little lambs.
Is there a source for zerumbone?
Margaret,
I am researching Zerumbone for Pancreatic cancer. You mention in your article that you could email the complete article on the testing
of the natural products that led to the discovery that Zerumbone was
another Hh signaling inhibitor.
Could you please send me a copy of the cited article. My concern is
the toxicity of the product and at what dosage it can be administered safely.
Thanks,
Robert
Richard and Robert:
As an MGUS patient, I try to keep current with the treatment alternatives out there. Because of the seeming lack of interest by traditional medicine in the study of zerumbone and cyclopamine, I have started a website, http://www.curingourselves.com, to facilitate “our own” clinical study of these products.
We now have a supply of zerumbone, and are trying to find a source of cyclopamine tartrate or -L-rhamnose, which seem to be the two most soluble– and thus bioavailable (??) forms out there.
We will make these compounds available at our cost (which will likely still be very expensive for CP in particular) if the purchasers will agree to share their results (anonymously, of course) for the purpose of getting a large sample pool and thus more accurate findings.
Thanks, Kevin Toman DVM http://www.curingourselves.com
I am delighted to see that others have an interest in healing themselves. The traditional medical establishment in the U.S.
acts as if they are doing everything possible to fight cancer, but in
fact use drugs that research has shown to be only marginally effective
in the battle. Alternative therapy that includes non-toxic time proven
phytochemicals like Curcumin and Zerumbone appear to be the best
avenue we have to hold cancer at bay until researchers understand
completely the various signalling paths that are misappropriated by the
cancer. I have noticed a great difference in how I feel when taking
8-10 grams of Curcumin as a daily regimen, and am both in awe and in
debt to Margaret for this wonderful blog.
Thanks,
Robert
Hi all– Wanted to check in with my results on Zerumbone re MGUS– which, sad to say, were unremarkable. I took 300 mg zerumbone orally once daily for 2 months with no improvement in my m-spike noted. An acquaintance with pancreatic cancer also tried zerumbone with no response. It is a crystalline powder that I ordered from KingHerbs and loaded into gelcaps. While I would love to be proven wrong, it appears that either there is a bioavailability issue or the zerumbone is being metabolized to inactive products. Comments from smarter folks appreciated… Kevin Toman
Hi,
Whatever happened to all the promising research done on zerumbone in 2008? I have not seen anything more on the subject. If it is the dietary bioavailability, couldn’t research still be carried out with intervenous route. Could it be that it would not be a money maker for drug companies? I hate to think like that but it really is a mystery why it was so promising and totally abandoned.
Laura
I got some rhizomes on Ebay a few months ago after reading this blog and planted them in a container. About 2 feet tall now with numerous srouts. Since it is basically ginger, not the supermarket variety, I’ll dig out some rhizomes when it gets a more full and start making tea. Should have a constant supply. Awapuhi as it is known in Hawaii has been used medicinally forever.