Tag: cyclopamine

Buon anniversariooooo!

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It’s our 9th wedding anniversary today.

In honour of this momentous occasion: a photo of two seals that we encountered on our way to Inner Farne Island. Ah yes, I forgot to mention that we also saw quite a large group of seals, some swimming about in the water, some lying all huddled together on a small island, enjoying the sun. A few swam quite close to the boat to have a better look at us…curious creatures, just like Stefano and me! 

Thanks to an MMA list member, I found out that a cyclopamine derivative called IPI-926 is in the preclinical trial stage. You can read more about it here: http://tinyurl.com/4skodf And if you don’t remember what cyclopamine is, have a look at my Pages on the right-hand side of your screen: I have a page on cyclopamine. The pharmaceutical company that produces IPI-926 hopes to begin clinical trials in the second half of 2008. Exciting times lie ahead!

Un bacione, moro, TVTB! 

New hedgehog inhibitor: zerumbone

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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! 

Blood tests, more on cyclopamine and…Cancer Vixen

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Blood tests. Last night I decided that a silly little fever wasn’t going to stop me from taking these tests. So this morning I got up at the crack of dawn, made sure I had no fever (the little coward vanished overnight, hah!), and set off for the hospital, where I met up with Sherlock. We were tested together and were out by 8 a.m. She had work to do so she headed home, while I went to another part of the hospital to have a breath test…ah, no, not what YOU are thinking, no siree! This test will determine if I am infected with Helicobacter pylori. In case you don’t know what I am babbling about, check out my page on Helicobacter pylori and MGUS. In a nutshell: it’s a bacterium that infects the stomach and can cause us a lot of grief, A LOT!, ranging from peptic ulcers to cancer.

A slight aside. Wikipedia provides a fascinating account about how H. pylori was discovered, or rather, rediscovered in the early 1980s more or less, by two Australian scientists, Warren and Marshall, who were the first to successfully culture it. They believed that most stomach ulcers and gastritis were the result of an infection caused by this bacterium and not by stress or spicy foods as had been previously assumed. To prove their point, Marshall drank a Petri dish of H. pylori and developed gastritis. A man after my own heart!  Gutsy! You can read the full story on Wikipedia.

Anyway, this was an interesting test. First, using a plastic straw, I had to blow some air into two vials, enough to steam them up. Then I had to drink something that tasted like very bitter lemonade (urea) and wait for a half hour. I then blew into two different vials. That was it. For details on how the H. pylori breath test works, see http://tinyurl.com/33nvay

I will have all my test results back in about three weeks. Probably a few of my values will be altered due to the cold I have been fighting (successfully, so far!!!), but I am hoping they won’t be TOO off. No worries.

A few words on cyclopamine. Yesterday I wrote to CT, asking the question posed by one of my blog readers (see my recent cyclopamine post) concerning water solubility. CT replied: I took cyclopamine tartarate which Logan labs claims is somewhat water soluble. Mice at UTMS took the regular cyclopamine orally for basal cell CA and it worked, so it must be getting absorbed. I note that is does mix well in water. In any event, my M-marker did go down. I will know more when I retest.

Cancer Vixen. While I was waiting to have my breath re-tested this morning, I began reading a book that Sherlock gave to me (grazie!), titled "Cancer Vixen," by Marisa Acocella Marchetto, a cartoonist for the New Yorker (etc.). At one point I almost laughed out loud. I wonder what the other patients sitting in the waiting room thought of me: a grown woman reading and chuckling over what looks like a…comic book!  (Not that I cared one whit, mind you!). Hehe.

Anyway, since you already know (if you have been reading my blog for a while) that I have a wacky sense of humour, you won’t be surprised to read that the part that thus far has amused me the most, and I am only on page 20!, is when she is told that she has an "abnormality" (referring to a breast tumour). Oh yeah, that’s a bit of really hilarious news, ujú ja ja ja ja ja jaaaaaa…ñaca-ñaca (that’s an "evil laugh" in Spanish, no kidding; you can find the most peculiar items in Wikipedia…), but I assure you that the cartoons are quite amusing, IF you have a warped sense of humour, that is!  

Well, I haven’t read any cartoons since I was in my teens, so this is fun, even though the subject itself (cancer!) isn’t that much…fun, admittedly! Oh, wait, another funny cartoon is the one depicting "possible cancer cells" in a petri dish, "magnified 3 gazillion times." Marisa makes them look like evil little green buggers sticking out their tongues and giving us the…finger. Good job, Marisa, so far. I will keep reading.

Update on cyclopamine

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Yesterday a myeloma list member reported his test results after five cycles of cyclopamine. He authorized me to post about it. If you have no clue as to what I am writing about, see my August 2 and 3 2007 posts about cyclopamine, or my permanent page (see my Pages on the right, and look under "Other anti-myeloma/cancer supplements").

Here are some details posted by the cyclopamine-taking list member (from now on, I will refer to him as CT, or cyclopamine-taker) took a water-soluble form of cyclopamine for a year and a half. More specifically, he took 200 mg of cyclopamine a day for 14-15 days at a time, every 2-4 months. His m-spike went from 1.0 (achieved after two stem cell transplants two and a half years ago) to 0.2, then to 0.1, and he is convinced that these decreases, the first since his transplants, were due to his cyclopamine intake. Coincidental? Possibly. He reported, by the way, no side effects. Indeed, he feels great.

Okay, but we should not get TOO excited about this substance. The main reason, at least as far as I am concerned, is that it costs an arm and a leg. I had the brilliant idea of seeing if I could order some and ask my parents bring it over to me when they fly to Italy for their regular summer visit, but when I saw what it cost, i.e. thousands of dollars, my eyes almost popped out of my head. No way I could afford it. CT has a cheaper source than what I found online, but it’s still way beyond my budget.

Another list member pointed out that he would be anxious about potential side effects that might not manifest themselves immediately, but perhaps 20 years down the road. But CT (good sense of humour!) said that he would be happy to survive 20 years with myeloma! Indeed. He added that he is well aware that there are possible risks involved in taking a substance that hasn’t been approved by the FDA, but after all, we are dealing with myeloma, not an ingrown toenail (my analogy, actually). So true.

CT reminded us that Dr. Matsui reported in April 2006 at the American Association for Cancer Research (AARC) meeting that cyclopamine caused differentiation of  myeloma stem cells. In other words, the myeloma stem cells were eliminated because they did not produce any more cancer stem cells. The stem cells turned into mature plasma cells that eventually died out. Normal cells were not affected, he reported.

For an interesting Science Daily article (2002) on cyclopamine, see: http://tinyurl.com/2zcwut

In PubMed there are 260 studies on cyclopamine. But there is not one clinical trial. Typical.

As usual, I hope this situation will change soon. If it does, I might be first in line!

Update on the update: with this post, I wanted to report on an interesting case, perhaps (I hope!) a crucial one in the battle against myeloma stem cells. I would like to underline, though, that I am not encouraging folks to take cyclopamine. Even though we aren’t pregnant sheep (if you are puzzled about that statement, read my page on cyclopamine: all will be clear ), we still don’t know if there might be harmful side effects (etc.). CT did report that he had none, which is extremely important. In sum, I think this substance should definitely be put on our watch-and-see list. Yes, indeedie!