Notching cancer stem cells

April 16, 2008 / / 4 Comments

A few days ago I made some connections between a couple of items that I read online and an "old" post of mine. I am still in the "could this possibly be true?!" stage (more like a daze, really). At any rate, I will anticipate a few of my findings today, even though I have only just begun my research on this topic and still have a few things up my sleeve. But let me proceed in chronological order.

On April 12^thand then on April 14^th, I read two Science Daily articles (http://tinyurl.com/4gcjyc and http://tinyurl.com/5h9jom) that reminded me of a rather superficial post I had written on Notch signalling last fall. That’s what started it.

But first, what is Notch signalling? The Science Daily articles tell us that the Notch pathway sends signals from a cell’s surface membrane into its nucleus. Those signals activate genes that instruct the cell to make proteins that perform various tasks. It helps regulate fetal development and is active in most organ systems throughout a person’s life.

A 2005 Science Daily article (http://tinyurl.com/55xlyx) discusses the role of Notch signalling in the development of T cells: no Notch = no T cells, it would seem. So this is a vital pathway. That is, as long as it doesn’t go whacky. But it does, sometimes.

Abnormal increases in Notch signalling can give rise to T-cell acute lymphoblastic leukaemias, and these increases are present in other cancers as well (myeloma is no exception, hah, figures!): Prior work has shown that increases in signals generated by Notch are important in certain human tumors, particularly some kinds of childhood leukemia, making Notch an attractive target for new cancer therapies.

Big problem, though: researchers were concerned that Notch inhibition might have a negative effect on the normal functioning of the healthy stem cells present in the bone marrow. Another “damned if you do, damned if you don’t” situation? Would the inhibition of Notch end up actually destroying the bone marrow? A very scary thought, based on the fact that Many scientists have long assumed that blood-forming stem cells need Notch signals to function properly. But let me note that this sentence was written a couple of years ago. Things have changed in the meantime.

A group of researchers from the University of Pennsylvania School of Medicine and colleagues has recently demonstrated that inhibition of Notch signalling will not mess up our healthy stem cells. They discovered that the Notch signaling pathway, which determines the development of many cell types, and is also implicated in some cancers, is not universally essential for the maintenance of stem cells. In fact, adult bone marrow stem cells do not require Notch signals. Super!

The University of Michigan Medical School has therefore begun a “groundbreaking trial” that combines chemotherapy with Notch inhibitors: The aim is to use so-called Notch inhibitors to attack cancer stem cells, the small fraction of stem cells inside a tumor that help it survive and that fuel its growth.

Let me highlight this sentence: Notch inhibitors attack cancer stem cells.

Okay, and here is my bombshell of the day…

Curcumin inhibits Notch signalling.

Blast, heat and cook…

April 15, 2008 / / 3 Comments

Even though it may seem that I am beginning to be obsessed with the evils of nanotechnology, I want to post about a story I read when I got back from work today. A story that concerned me. In fact, the more I read about nanoparticles and nanotechnology, the more I feel troubled. Things are just happening too quickly. We start with probably toxic nano-socks and stain-resistant nano-khakis and end up with nanoparticles being shot into tumours, which are then “cooked” with “harmless radio waves.” But are these waves really so harmless? And what about the nanoparticles travelling through us?

I went to read the story (the link was provided by a myeloma list member, by the way): http://tinyurl.com/4ldegs This page also provides a link to another page, which lists the potential dangers of nanotechnology: http://tinyurl.com/52xrge (Oh, and this story, that I learned about through a different list member/also friend, was featured on 60 Minutes on April 13th, see here: http://tinyurl.com/4buscb)

Let’s look at the first link…first. This type of cancer treatment is said to be noninvasive, and uses nontoxic radio waves combined with gold or carbon nanoparticles, which have a long history of medical use. A long history of medical use? Really? Let’s read on: Nanoparticles made of gold, carbon and other materials can move through the bloodstream and through cell walls, allowing for efficient drug delivery, or to act like a homing devices for research purposes.

Now, I don’t know about you, but I am not thrilled at the idea of any of these itsy bitsy particles travelling through my bloodstream. Hmmm.

Then, When the gold nanoparticles are inside the malignancy, a blast from a radio-frequency generator causes them to heat and cook the cancer cells. Blast, heat and cook? Am I the only one who finds this alarming?

The lead researcher thinks that human trials could begin within three years. The cancer treatment thus far has been tested only on animals (sigh!) and human cells. It apparently ignores healthy cells, but that depends on the type of cancer. There were also no “noticeable” side effects. Well, duuuh!, that’s because the side effects were…nano-effects!

The second link takes us to an article written in 2005 about the potential hazards of nanotechnology. A scary (to me) sentence depicts these particles as just atoms wide and small enough to easily penetrate cells in lungs, brains and other organs.

A lot of money is being invested in this technology (the U.S. federal government was spending about $1 billion/year on nanotechnology back in 2005, I tremble to think of what that amount is today), but how much is being invested in safety tests? A fraction, apparently.

The other day I read a Science Daily article on the dangers posed by nanotubes, and it just so happens that today’s article points out that these nanotubes have been found to be toxic to animal cells and that There are fears that exposure can cause breathing problems, as occurs with some other ultrafine particles, that nanoparticles could be inhaled through the nose, wreaking unknown havoc on brain cells, or that nanotubes placed on the skin could damage DNA. Aren’t we surrounded by enough human-created pollution? Why introduce more of it into our bodies…?

Not to speak about the possible, indeed probable damage to the environment.

But who cares about the environment? So what if this nanostuff gets into our water, into our food and, indeed, under our skin (via innocent-looking sunscreen; by the way, for a list of sunscreen products that contain or may contain nanogunk, go to http://tinyurl.com/3vz5rc, which is also the website from which I got the image on the left)?

After all, the goal of business is to make a profit, right?

Immortal?

April 14, 2008 / / 9 Comments

My blog reader/friend Paul raised a very interesting question, for which I didn’t have a satisfactory answer, so I asked the general MMA myeloma patients list (link here on the right-hand side). Based on his comment (see my recent post on zerumbone), my question was: do cancer stem cells die?

I received more or less the following answer (in italics; I edited small parts of it) from a list member/doctor who takes cyclopamine and knows a lot about stem cells:

Stem cells, whether healthy or cancerous, are supposed to last a lifetime. Do some die off? Yes. For instance, the main reason people age is that they gradually lose their healthy stem cells.

But cancer stem cells have a lot of telomerase, which keeps their telomeres long, and keeps them essentially immortal. Cyclopamine (extracted from the corn lily, see photo) causes the cancerous stem cells to differentiate and turn into mature cancer cells without making more copies of cancer stem cells. (Aha!)

Now, mature cancer cells (plasma cells in myeloma) do die off. They are not immortal. So, in theory, if you kill off all the cancer stem cells, then eventually the cancer cells die, too. This is the basis of using cyclopamine.

Some research shows that some cancer cells may be able to turn back into cancer stem cells. That could be a problem, but if you target both the cancer stem cells and the mature cancer cells, then the problem is solved. Of course, continuous treatment of the cancer stem cell would also take care of the problem.

In a nutshell, then, cancer stem cells are immortal. But if we manage to block certain signalling pathways, we can turn them into mortal cancer cells. My haematologist said that myeloma cells may live for weeks or even months. That depends on a lot of factors. But eventually, they kick the bucket. This makes me wonder if zerumbone has the same effect that cyclopamine has on cancer stem cells…that is, does it turn them into regular cancer cells? Good question. No answer…yet.

Fascinating topic. In addition, Paul’s comment led me to make a series of connections that I had begun to make some months ago, but then had set aside only to rediscover this morning. Thank you so much, Paul!

Oh, I do hope my current bit of research will lead to some useful information. Okay, I have to go feed my cats now.

Conventional doctors turn holistic

April 13, 2008 / / 1 Comment

I am taking a break from zerumbone today, except for leaving a few comments on yesterday’s post. I will instead have a look at a recent Cancer Compass article (http://tinyurl.com/4a4wxe), which begins with the description of a Reiki session. I have never had any formal training in meditation or participated in a Reiki class, but I have created my own form of meditation and sometimes use Reiki music to help clear my mind of the daily clutter. Very helpful.

As the article suggests, Reiki is part of what is called complementary treatment or integrative medicine, which combines conventional and alternative treatments. Some hospitals are now offering complementary and even alternative treatments to patients. Extraordinary, don’t you think?

And some doctors are following courses in integrative medicine, like Dr. Edward Planz, a heart surgeon, who graduated from an Internet-based two-year fellowship in integrative medicine through the University of Arizona. What inspired him to explore this field were his bypass patients’ questions about supplements and other forms of alternative medicine. Since he couldn’t give come up with any answers, he studied mind-body interactions, nutrition and botanicals. A doctor after my own heart (pun intended…)!

This proves how vital it is for us (patients) to ask our doctors challenging questions.

There is another good example in the article. Dr. Edmond Zlotea, whose approach is to take care of the whole person — structural, nutritional and emotional. […] Stress, he said, is one of the major causes of illness. […] "It’s like peeling layers of an onion," Zlotea said. " … The onion’s not too healthy on the outside, but it is on the inside. You just have to peel the layers of stress from the onion."

The article points out that taking this attitude, a holistic attitude, gets doctors into trouble with the pharmaceutical industry. As Dr. Zlotea points out, pharmaceutical companies have turned something that’s supposed to be about healing into a business." No kidding.

Well, the times, they are a’changing…or at least may be a’changing…after all, Rome wasn’t built in a day…!

New hedgehog inhibitor: zerumbone

April 12, 2008 / / 14 Comments

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!

Hold on to your socks!

April 10, 2008 / / 6 Comments

In spite of the title, this is actually going to be a serious post. Remember my recent one on nanotechnology? Well, this is sort of a follow-up. I just finished reading a rather alarming April 7 Science Daily article (see: http://tinyurl.com/4s5zoh) on “toxic socks.” These are special socks permeated with nanoparticle silver, which has antibacterial and odour-fighting properties.

Problem is, if you buy these socks (or anything else containing nanosilver), you won’t be able to wash them. Ever! If you forget and throw them into the washing machine, tiny silver particles will probably be released into the waterwaste system and end up flowing into natural watercourses where they could have unwanted and deleterious effects on the organisms living in the water, and possibly, eventually, on us, too.

Two Arizona State University researchers brought the issue of nanosilver to our attention after conducting a recent experiment. They bought six pairs of no-smell socks, one from the UK (!), soaked them in a jar of room temperature distilled water, shook the contents for an hour and tested the water for two types of silver — the harmful "ionic" form and the less-studied nanoparticle variety. "From what we saw, different socks released silver at different rates, suggesting that there may be a manufacturing process that will keep the silver in the socks better," said Benn. "Some of the sock materials released all of the silver in the first few washings, others gradually released it. Some didn’t release any silver."

So if you wash these socks, possibly even large amounts of nanosilver will eventually end up in lakes and rivers. Ionic silver, the dissolved form of the element, does not just attack odor-causing bacteria. It can also hijack chemical processes essential for life in other microbes and aquatic animals. It can, for instance, kill fish by seeping into their gills, thereby disrupting their blood and tissue chemistries. And what happens to our gills and blood/tissue chemistries if we eat teenysilver-ridden fish?

Oh boy, let me tell ya, I wouldn’t go near these socks, let alone touch them with my bare hands or put them on my feet! I will also never ever (never!) buy infection-fighting bandaids (oh yes, nanosilver is in those, too!). And, if you happen to be in the market for a new washing machine, avoid the ones that advertise “silvercare.”

After reading this piece, my advice is: let your socks smell a bit. It seems like a tiny price to pay compared to the potentially very negative environmental impact of the no-smell silver socks. Talk about nanoCRUD!

Omega-3 and angiogenesis

April 9, 2008 / / 9 Comments

The April 1 issue of “Blood” has an interesting study that examines the role played by n-3 polyunsaturated fatty acids (PUFAs, gotta love that acronym! Oh, "n" stands for omega, by the way) in angiogenesis, which, in just a few words, is a process whereby tumours develop a blood supply and are able to grow and live as happily as clams at high tide. So clearly one of our goals should be to block the blood ( = food) supply to tumours. As we have seen, a couple of simple ways we can do that is to take curcumin and drink coffee (probably not at the same time, though I haven’t tried doing that, I admit…).

The full study (abstract: http://tinyurl.com/2nvqnm), which I was able to read thanks to Sherlock

tells us that n-3 PUFAs inhibit the formation of new blood vessels (angiogenesis), a critical process that affects tumor growth and dissemination. So we can now add n-3 to our list of angiogenesis inhibitors. Excellent.

But what about n-6 fatty acids? The abstract tells us that n-6 PUFAs stimulate angiogenesis. Does that make n-6 one of the bad guys? That’s what I thought, at first. But no, we need both these fatty acids in order to be healthy, so eliminating n-6s from our diet would be a very VERY bad move.

What we lack is BALANCE between the two omegas. Read this: In terms of the consequences for human health, it has been shown that Japanese who migrated to the United States and acquired the local dietary habits leading to an increase in the dietary n-6/n-3 PUFA ratio of 16:1 resulted in health problems in the migrants similar to those that already existed in the local population. Sixteen to one! That’s astounding. Even more astounding: the ideal balance should be 1:1, at the most 4:1. But the average North American diet, and probably European by now, ranges from 11:1 to 30:1. Yikes!

According to Andrew Weil, M.D., This dietary imbalance may explain the rise of such diseases as asthma, coronary heart disease, many forms of cancer, autoimmunity and neurodegenerative diseases, all of which are believed to stem from inflammation in the body. The imbalance between omega-3 and omega-6 fatty acids may also contribute to obesity, depression, dyslexia, hyperactivity and even a tendency toward violence.(see: http://tinyurl.com/4s32fc; see also: http://tinyurl.com/565h8n).

Now, what happens when we ingest n-3s and n-6s? They get converted by so-called PUFA bioconversion enzymes. Otherwise, these fatty acids would not be of any use to us at all. The researchers state that their findings suggest that n-6 and n-3 PUFAs compete for enzymes involved in PUFA biotransformation. It is widely believed that PUFA bioconversion enzymes have a greater affinity for n-3 PUFAs so that their biotransformation is favored when the dietary n-3 PUFA intake is high. This simply means that the two omegas compete for the attention of these bioconversion enzymes, and n-3s happen to be the winners.

Hmmm, interesting little fact that I didn’t know: n-3 PUFAs inhibit NF-kappaB AND Bcl-2. Well, well. Another good reason to include them in our diet.

At any rate, our bodies are not able to produce these fatty acids from scratch, and in fact that is why they are called "essential" (essential for health, but cannot be made inside the body), so we need to get them from our food.

Dietary sources of n-3s: mainly cold water fish such as salmon, herring, anchovies, but be careful about the potential presence of heavy metals, PCBs and dioxin (!); also, but to a lesser degree, flax, pumpkin seeds, walnuts, pecans, butternuts, nut oils, as well as the seeds of: chia sage, kiwi, lingonberry, black raspberry. For more info: http://en.wikipedia.org/wiki/Omega_3. By the way, today I learned that mercury does not get stored in fish oil (only in the tissue). How about that? I also learned that some manufacturers are able to purify fish oil via molecular distillation, which increases the cost, but who wants to be swallowing dioxin or pesticides, after all? I would rather pay more for a high quality product. So, do your research, watch what you buy, and don’t go for el cheapo.

Fanatic Cook tells us that walnuts, soy and canola oil contain more n-6 than n-3. She has some excellent pages on n-3, including this one (http://tinyurl.com/22xd95), where she informs us that only a TINY part of n-3s from nuts and non-animal sources has anti-inflammatory effects. She explains why. N-3 has to be converted, and, as she notes, if you want to make sure you’re getting enough of the active forms of n-3, it’s best to eat an animal that has done the conversion for you. Interesting. Okay, I am beginning to see more fish in my future. We are lucky to get our fish from a small Tuscan fishing cooperative, so we can be sure that the fish is fresh and that no mass fish slaughters take place in the Tyrrhenian Sea. That’s always a consideration for my tender heart.

Dietary sources of n-6s: poultry, eggs, cereals, whole-grain breads, baked goods, most plant-based cooking oils (sunflower, corn etc.), nuts, borage oil. See also: http://en.wikipedia.org/wiki/Omega_6

In sum, have I reached any conclusions? Well, more research is needed, but I think I will switch from flaxseed oil to fish oil or, perhaps even better, krill oil. The diet of cold water fish consists mainly of krill (a step down the food chain, see image on the left), and the main advantage of swallowing krill oil is that it contains fewer pollutants; a disadvantage is that it has less n-3 compared to its predators. Oh well, we can’t have everything!