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!