Turmeric compound boosts regeneration of brain stem cells

I’ve been working on a rather complicated post (don’t ask…) but decided to take a break today, after what happened in Paris yesterday…No words can express my horror..all I can say is: “Je Suis Charlie.”

It’s hard to focus on anything else…but earlier today I came across an intriguing Science Daily article on a study showing that another compound of turmeric — not curcumin, but something called ar-turmerone — “promotes stem cell regeneration and differentiation in the brain.” And so I decided to post the link: http://goo.gl/rNXok5

In addition to imbibing vast quantities of curcumin every day, I also use turmeric, the spice, in my cooking. Often. And now I’m VERY glad I do!

Two new AML stem cell killers

In my June 11 post I mentioned reading about two compounds that effectively eradicate AML at the bulk, progenitor and stem level: celastrol and 4-hydroxy-2-nonenal or HNE (AML stands for acute myelogenous leukaemia, by the way). Well, thanks to Sherlock Smiley face, I was able to read the whole University of Rochester/University of Pennsylvania study. The abstract can be seen here: http://tinyurl.com/6ltvw5


The full study begins with an acknowledgment of the importance of cancer stem cells, or CSCs, for studies of basic tumor biology and the development of improved therapies. Like normal stem cells, CSCs are thought to reside at the apex of a developmental hierarchy and are responsible for the continued growth and expansion of bulk tumor populations. Consequently, the biological activity of CSCs may contribute to initiation, maintenance, and relapse of at least some forms of cancer. Yes, this sounds all too familiar…


The researchers further comment that several studies have shown that AML stem cells (AML-SCs) are refractory to commonly used clinical agents such as cytarabine and anthracyclines, thereby further supporting the hypothesis that malignant stem cells represent a probable reservoir from which disease relapse may occur. In vitro studies, they continue, have shown that the combination of the chemotherapeutic drug idarubicin and the proteasome inhibitor MG-132 can effectively eradicate leukemia stem cells via a mechanism involving concomitant inhibition of nuclear factor-kB (NF-kB)–mediated survival signals and induction of oxidative stress.


Then they discuss parthenolide (PTL), a substance that can ablate AML-SCs as a single agent. As a single agent, mind you! Impressive. They add that the SC-killing mechanism is similar to the one used by the idarubicin and MG-132 mixture, and that is: combined inhibition of NF-kB and induction of oxidative stress, thus indicating that common biological principles underlie the anti–AML-SC effects of these agents despite their chemical diversity.


The researchers decided to explore other AML stem cell killing possibilities using gene expression signatures. They examined the natural antileukemia characteristics of PTL, which has been shown to induce very potent and specific effects, mediating rapid death of AML-SCs, but not normal hematopoietic stem and progenitor cells, looking for other substances that provoke a similar response in cancer stem cells. They then tested those compounds against AML stem cells.


For this purpose, they used the GEO or Gene Expression Omnibus, a sort of humongous gene expression warehouse. To their surprise, they found a recurring and chemically diverse group of compounds that mimic the PTL gene expression pattern and, like PTL, are capable of ablating AML cells at the bulk, progenitor, and stem-cell level. The sentence that follows is also important: As with PTL, the mechanism of action for these new compounds involves concomitant inhibition of the NF-kB survival signal and induction of oxidative stress, suggesting their general importance in targeting AML stem cells. Sorry to keep repeating “NF-kB plus oxidative stress,” but this is a crucial point, methinks.


The researchers identified and tested four compounds, including the two that I mentioned the other day and that inhibit NF-kB and proteasomes. These two were found to have molecular characteristics comparable to those of PTL. I should note that these compounds, while known for their anticancer activity and for their ability to inhibit NF-kB, had never before been tested for their specific ability to target leukemic stem cells.


By the way, the other two compounds, gedunin and hemin, did not target the AML stem cells and were therefore discarded.


In conclusion, this study is remarkable not only because of the discovery of two new compounds that exterminate AML stem cells, but also because a gene expression database was used to identify potentially useful compounds. Very very interesting approach…

Update on cyclopamine

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!

The myeloma tap: part I

This post was way too long so I decided to cut it in half. I will post the second part tomorrow. Only then will today’s title make complete sense.

Anyway, I have it, I have it! Yes, the FULL recently published Johns Hopkins myeloma stem cell study that I mentioned a couple of days ago. Okay, I confess that I have had it in my possession since last Sunday, when a very kind blog reader (thank you thank you thank you!) sent it to me, but just haven’t gotten around to writing a post about it. The study, by the way, was conducted by a team led by Dr. William Matsui and published in the January 1 2008 issue of “Cancer Research.” You can view the abstract here: http://tinyurl.com/2yuru9.

Before I go on, though, I wanted to mention that another blog reader posted an interesting New York Times article on the controversy surrounding the cancer stem cell theory and other interesting info, so if the issue of stem cells is your cup of tea, please go read Carla’s comment on my “Stem cells and myeloma” post, Jan 12th.

Back to us. I have to admit, reading this stem cell study was not exactly as fun and easy as reading one of the Harry Potter books, but I found it almost as engrossing. The study begins by providing a bit of background, including this: “Early studies examining a murine model of multiple myeloma suggested only a minority of cells were capable of clonogenic growth.” Hmmm, so only a tiny percentage of myeloma cells can clone themselves…I didn’t know that. I thought they were all capable of creating clones. Live and learn.

Myeloma stem cells are mentioned in a 1977 study (full text: http://tinyurl.com/2d8z3n), which, by the way, shows black and white photos of myeloma cells for those who might be interested. Anyway, according to the Johns Hopkins investigators, this early study showed that “the cloning efficiency of primary multiple myeloma specimens was 1 in 1,000 to 100,000 cells. To date, it has remained unclear whether these clonogenic cells are distinct from the plasma cells that constitute the majority of tumor cells.”

Then, in 2004, Dr. Matsui et al published a study (full text: http://tinyurl.com/2233wp) in “Blood” on clonogenic myeloma cells. Clonogenic, by the way, has two meanings: 1. “giving rise to a clone of cells” and 2. “arising from or consisting of a clone.” I went through the 2004 study, which reported that “highly clonogenic cells from both human MM cell lines and primary patient samples do not express CD138, but rather markers that are characteristic of B cells.” This rather baffling sentence will, I hope, become clearer after the upcoming section on CD138 (and part II, which I will post tomorrow, should also help in that sense). The 2004 study also suggested that, like chronic myeloid leukaemia or CML, “MM is another example in which cancer stem cells are a rare cell population that is distinct from the differentiated cells that comprise the bulk of the disease.”

CD138. Now I am going to delve into some rather difficult material that has to do with this thing called CD138. Also known as syndecan-1, CD138 “is “a heparan sulfate proteoglycan expressed on the surface of, and actively shed by, myeloma cells.” I know, I know…Let’s see if this will clarify matters: proteoglycans are “glycoproteins but consist of much more carbohydrate than protein; that is, they are huge clusters of carbohydrate chains often attached to a protein backbone,” according to Prof. Kimball’s Biology Pages. (Hmmm, lots of carbs plus some protein…pasta with meat sauce! )

Seriously though, it doesn’t really matter if we don’t completely grasp what CD138 is. What’s important is that we understand the following excerpt from the 2004 Johns Hopkins study. CD138 “is the most specific marker for normal and MM plasma cells. However, normal CD138+ plasma cells appear to be terminally differentiated and unable to proliferate, and there have been few studies using this marker to study the proliferative capacity of MM cells.”

Not the easiest stuff to digest, eh! Well, let’s see if I can explain what CD138 is in a few simple words (if I make any mistakes, please let me know): in sum, CD138 is a thingie (ok, a proteoglycan) sticking to the surface of regular myeloma cells—the ones, that is, that are NOT able to clone themselves. These are the CD138 "plus" myeloma cells. Patients whose myeloma cells release, or "shed," CD138 (CD138 "negative" cells) into the serum have a worse prognosis than those whose myeloma cells still have it. Hence it is a helpful prognostic marker (for more info, see this 2002 “Blood” study: http://tinyurl.com/2h26uq). CD138 levels can be measured in MGUS patients, too (see this 2006 "Neoplasma" abstract: http://tinyurl.com/yr9vzd).

A September 2007 “Blood” study (see abstract: http://tinyurl.com/2slg3t) confirms that “High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis.” So again we see that if CD138 is shed into the myeloma “microenvironment,” this is bad news for us (poor prognosis etc.). Interesting aside: this is true for CLL patients as well (see this January 2008 abstract: http://tinyurl.com/3ap8ba). Connections, connections.

Ok, that’s it for today! Phew.