Adenoviruses, CD40 and Myeloma

Well, it seems that I may stand corrected. In my October 8th post on CD40, I mentioned my doubts concerning the possible use of a modified cold virus delivery system for myeloma patients, but yesterday morning I read a few items that, hmmm, may have changed my mind. I will proceed in order.

All plasma cells express CD40, but that is not the case with all myeloma cells. According to a 1994 French Blood study (see: http://tinyurl.com/ywcyv4), two-thirds of myeloma patients express CD40. That means that one-third are CD40-. By the way, in case you had any doubt concerning the importance of CD40 for myeloma, read this excerpt: …patients with progressive myeloma present a high level of CD40 expression.

Regardless of whether your myeloma expresses CD40 or not, though, the important concept contained in a 2002 Blood study (see: http://tinyurl.com/ytv929) is that we should be able to stimulate our immune systems to react against the malignant cells if we are able to deliver a transgenic (genetically modified, basically) form of CD40L (= CD40 ligand or CD154) to either type of myeloma cells, whether it has CD40 on its surface or not. The study ends: because our results show that the interaction with CD40 antigen on tumor cells is neither universal nor required for the immune enhancement mediated by transgenic CD40L, the molecule may be of therapeutic value in both CD40+ and CD40- forms of the disease. So all bases are covered. Excellent.

Now, if we connect this study with the modified cold virus theory, we may have a delivery system, a system that is being tested in clinical trials for other types of cancer right now. I am getting to the good part, hold on.

I did research for and wrote this post after reading two very interesting Ph.D. thesis abstracts (Baylor University). The first, dated February 2007 (abstract: http://tinyurl.com/yqwr6l), is titled Anti-tumor properties of CD40 ligand when delivered as a transgene by the conditional replicative oncolytic adenovirus AdEH to breast cancer cells (try saying that out loud without stopping to take a breath!). The abstract informs us that a potential limitation of CD40L therapy is systemic toxicity. The good news, however, is that this toxicity can apparently be overcome by using an adenovirus, which is essentially a virus that causes upper respiratory tract infections.

Ahhh, a modified cold virus, perhaps? 😉

I have requested authorization to read the full text of the second Ph.D. thesis, dated March 2007 and titled: Growth inhibition of human multiple myeloma cells by a conditional-replicative, oncolytic adenovirus armed with the CD154 (CD40-ligand) transgene (abstract: http://tinyurl.com/25dsdk). The abstract informs us that for targeted delivery of CD40L, we have constructed a conditional-replicative adenoviral for delivery of the CD40L transgene (AdEHCD40L). So here we have a sort of Federal Express delivery van, that is, an adenoviral delivery system. The van is supposed to deliver a “lethal package,” that is, a genetically modified form of CD40L, called AdEHCD40L, to its CD40 “customer” located on the surface of myeloma cells. The delivered transgene, our FedEx package, then inhibits the growth of CD40+ human myeloma cell lines. Simply put, adenovirus plus modified CD40L equals no myeloma cell growth.

I admit that I am becoming a bit obsessed with these darned molecules. When I was a child, many many years ago!, I used to spend hours putting puzzles together. The more complicated and the more pieces there were, the better. Well, this molecule business is like a big virtual puzzle. Every day I seem to come upon a new piece of the puzzle. I will, however, stop before my brain melts.

Not yet, though!

Naturally Targeting CD40

Well, this CD40 project (see my October 8th post) is going to be time-consuming and involved, and I am not even sure how much headway I will make with it, as I am a linguist by trade, not a molecular scientist (sigh). Well, we will see. For now, I did discover that CD40 is inhibited by a few natural substances–and perhaps by many more that have not yet been tested in that sense–including parthenolide (PTL) and honokiol (HNK). Today I will focus on these two substances. Honokiol, by the way, in addition to downregulating CD40, was found to decrease IL-6 levels, a phenomenon that I had already discussed in my May 12th post on honokiol and multiple myeloma. For more information on these two substances and myeloma, please scroll down my Alternative Research Pages (right-hand of your screen). I would like to mention that I was able to consult the full version of the following (two) parthenolide and honokiol studies thanks to a dear friend (grazie, Sherlock!).

The first study (see abstract: http://tinyurl.com/27ag9l), published in 2002 in the Journal of Allergy and Clinical Immunology, examines the effect of parthenolide on dendritic cells (or DCs), which are immune system surveillance cells that originate in the bone marrow and control the functions of B and T lymphocytes. I looked up dendritic cells and myeloma and found that, according to an Italian study published in Blood in 2002 (see: http://tinyurl.com/22f9cp) , these cells are functionally defective or impaired in myeloma patients (trust me to be the bearer of good news, huh? Well, I wasn’t too thrilled by this discovery, either ). The Italian study also reports that IL-6 has an immunosuppressive role in cancer patients by inhibiting the development of DCs. The latter statement is off-topic (nothing to do with parthenolide, in other words) but worth mentioning, in my view, because the authors soon thereafter suggest that the IL-6 inhibition of dendritic cells may be the mechanism whereby myeloma cells escape recognition by our immune system. Food for (future) thought.

Back to the 2002 parthenolide study. It is very technical, which made it very hard for me to follow. At any rate, as the abstract anticipates, parthenolide was found to downregulate the co-stimulatory molecule CD40 in a concentration-dependent manner, which is important news for us. I am beginning to think that even though parthenolide is another blood-thinner like curcumin, it might be worth my while to give it a try. I intend to ask my haematologist if she has access to DMAPT (see my October 3rd post).

The second study deals with honokiol (see abstract: http://tinyurl.com/yqoyn6) and was published in The Journal of Immunology in 2007. It examines inflammatory conditions such as rheumatoid arthritis (RA) but contains information that could be relevant to myeloma and perhaps other cancer patients as well. Here are a few of the more relevant and understandable (!) excerpts: A number of conditions are associated with the chronic inflammation and elevated levels of TNF-alpha and IL-6 seen in RA, including heart disease and cancer. Although the gastrointestinal tract is one of the most common sites of such cancer induction, a similar mechanism can also been found in plasma cells, leading to lymphoproliferative changes, lymphomas, and myelomas. [TNF-alpha is a growth factor for myeloma, as is IL-6.] This statement offers nothing new to those of us who were already aware of the inflammation-cancer connection. The study goes on to explain, however, that CD40, a member of the TNFR superfamily, is a key costimulatory molecule in T-B cell interactions, promoting the up-regulation of inflammatory cytokines such as TNF-alpha and IL-6 and autoantibody production. [TNFR stands for tumor necrosis factor receptor.] Now, I don’t recall ever having read that CD40 can activate IL-6. Interesting. And definitely here we have another strike against CD40.

Treatment with honokiol inhibited the activation of both of these myeloma growth factors, i.e., TNF-alpha and IL-6. This sentence deserved its own separate paragraph!

In the study’s Discussion part, we can read that CD40-mediated B cell activation, a key component of CIA pathogenesis, was inhibited by HNK treatment, and TNF-alpha and IL-6 were diminished in a dose-dependent manner, without decreasing IL-4 or IL-10 secretion. The support of IL-4 and IL-10 production by HNK is particularly beneficial given the established anti-inflammatory effects of these two cytokines. [CIA stands for collagen-induced arthritis.] I looked up these two cytokines, which is one big reason why this post took forever to write!, and, of the two, IL-10 apparently promotes the proliferation of myeloma cells. So the fact that it is not inhibited by honokiol doesn’t seem to be such a good thing. [I should note that high levels of IL-10 are, however, beneficial in other types of cancer, e.g. breast cancer.] And indeed, if we take another look at the above-mentioned Italian study, we find that IL-10 is produced by myeloma cells and could possibily inhibit the “differentiation and function” of dendritic cells. But perhaps this negative factor for myeloma is offset by the other beneficial effects of honokiol, such as its ability to inhibit NF-kappaB: It is consistent with the anti-inflammatory effect of HNK on CIA to see the dose-dependent inhibition of the transcriptional activators NF-kB and AP-1 in B cells.

The researchers add that they saw an increase in the amount of IgM after treatment with honokiol, which may have resulted from the above-mentioned NF-kB and AP-1 inhibition. We already know about NF-kappaB, but I would like to point out that AP-1 is also an evil transcription factor. At any rate, since honokiol increases the levels of IgM, let’s have a quick look at this immunoglobulin: it is found on the surface of B cells and gets released into the bloodstream during the body’s initial response to infection. Hmmm, perhaps if my IgM levels had been higher than they are at present, I wouldn’t have succumbed recently to that stupid germ. Bring on the honokiol! 😉

There is much more information, but I think this post is overwhelming enough so I will stop here. I am also looking at a couple of other natural substance studies in connection with CD40 but don’t yet know if they will be relevant. Okay, I need a nap now. Just kidding! 😉

Curcumin for Cats

Today I have been again immersed in the CD-40 natural antagonist literature, but the post is still not ready. So, in the meantime, I have decided to post a couple of items on another topic that I am very interested in (for two obvious reasons!): cats and curcumin.

A blog reader who unfortunately has an ailing cat sent me a private message earlier today asking if I had ever heard of curcumin being given to animals. Well, it just so happens that I have. Another blog reader, Vince, treated his cat, diagnosed with myelofibrosis, a blood disorder, with curcumin. She is alive and well today. You can read Bella’s amazing story here: http://www.mo-driver.com/bella.htm

I would have no hesitation in giving curcumin to one of my cats in case of need. But how much curcumin? Well, my blog reader sent me a file about a kitty called Bud who was given curcumin to treat FIV (feline AIDS). The website is: http://goo.gl/KV4jg (updated in Jan 2012). The information on curcumin dosage is as follows:

“Because it stimulates bile flow, contraindicated if there is bile duct blockage or gall stones. Should be taken with food. to minimize irritation. One source places a therapeutic feline dose of curcumin at 50-100mg daily and cites 100mg/kg as a benchmark ulcerogenic dose in ‘animals.’ (Human dosage: 2000mg curcumin, 20mg piperine, divided three times daily; Bud’s Dosage: 225mg curcumin, 6mg piperine, divided three times daily between meals; second round, 200mg with piperine and 50 GDU bromelain, divided twice daily with meals.).”

My concern: six mg of piperine sounds like a lot for such a small dosage of curcumin. I wouldn’t give my cat that much. Indeed, I might even skip the piperine and try something else (some sort of fat that my kitty would find palatable).

I also found the following, which confirms the 50-100 mg/kg dosage: “At very high doses (100 mg/kg body weight), curcumin may be ulcerogenic in animals, as evidenced by one rat study. […] Feline dosages are in the range of 50-100 mg daily of curcumin and approximately one-quarter teaspoon daily if using whole turmeric.” (see: http://goo.gl/xQaxl)

I will look into this matter more closely once I emerge from the world of molecular science.

Bed Cats

Today I read studies on a few natural substances that inhibit the co-stimulating molecule CD40, but the post isn’t ready yet. Perhaps tomorrow.

Piccolo, Priscilla and Peekaboo together! October 10, 2007In the meantime…today it just so happened that I managed to take a few photos of three of our cats lying together on our bed. The missing cat is Puzzola, our eldest cat, who mostly inhabits the upper quarters of our house. I am trying to get a shot of the four cats together, but it’s very difficult. At mealtimes, they are too excited, jumping over one another and running around for me to get a decent shot. Oh well! This is close enough!

Quercetin and Curcumin Potion

I wanted to mention that a couple of days ago I began mixing quercetin powder with my chocolate curcumin “ganache.” By the way, I bought the quercetin powder from Supplemental Health Formulations (see Curcumin Brands/Sources for info on SHF) about a year or so ago.

Quercetin powder and two types of curcumin powderHere is a photo portraying the three powders I threw into today’s brew. Left: two grams of quercetin. Top right: C3 Complex curcumin, four grams. Bottom right: SHF curcumin, one gram. I hope the photo is clear enough to show the difference in colour between the two types of curcumin.

As for flavour, well, this mixture tastes like a very rich (thanks to the double cream!) hot chocolate with a spicy edge. Very very nice. That is one reason why I hope that this method will work for me. 😉

Another, perhaps more important reason, one that I have mentioned on a previous occasion, is that mixing these powders into a liquid makes me feel a bit like Harry Potter putting together a healthful potion. It gives me a sense of active participation in the fight against my malignant cells. And, as I watch the powder dissolve and blend with the liquid, I have the time to visualize this mixture as it eventually encounters and kills some of my myeloma cells. I also like the feel of the thick drink as it goes down my throat, coating my tongue and painting it a rather bright shade of orange in the process. I know, I know, this must sound terribly silly. But I don’t get the same psychological feeling of power when I swallow curcumin capsules. Ahhh, it’s hard to explain. There’s only one thing to do: try it for yourself! 🙂

Modified Cold Virus May Kill Cancer Cells

I have decided to keep my cold, which I no longer see as a nuisance. Hurray for cold viruses! Ok, ok, I am being a tad (!) facetious. 🙂 Seriously, now. Yesterday morning, by chance, while looking up the most recent news on parthenolide online (nothing new to report since my October 3 post, by the way), I came across an interesting website, Cancer Research UK (http://tinyurl.com/2xh2wc). Its list of articles included one with my blog title, i.e., Modified Cold Virus May Kill Cancer Cells. Hmmm, intriguing title, I thought, so I clicked on the link and read that researchers from Birmingham University have developed a genetically modified form of the cold virus, a form that will not replicate (i.e., it won’t make us cough or sneeze) but merely serves as a vehicle to transport a human protein called CD40L to a cancer cell. Here it sticks to another protein, called CD40, which is present on the surface of many types of cancer cells (breast, liver and skin cancer, to mention a few). And the result of this sticky business? Apoptosis!

I could have stopped at that, but no, I just had to see if CD40 is present on the surface of myeloma cells. It is. So I dug deeper. Mamma mia! What a headache. I admit that I find myself more than a bit overwhelmed after being fully immersed in molecular science research for the past 36+ hours. So many studies, so much virtually incomprehensible technical lingo, so little time (and desire!) to earn a degree in biology and chemistry! 😉 I have now come to doubt that this “cold vehicle could be useful to myeloma patients (see below). In fact, this morning I almost threw away all my research and writing, but, to be honest, the CD40 topic was interesting, and the targeting of this protein may be relevant in the near future conventional treatment of myeloma, so I edited out some of the more convoluted stuff and decided to give the topic a quick whirl.

CD40 is an interesting molecule. It is present, at low levels, also on the surface of healthy cells, for instance of B cells (immune system cells). Under normal circumstances, I read, it is supposed to defend us from the attacks of viruses, bacteria and harmful substances and can even provoke apoptosis in tumour cells. However, it does not always perform as well as it should, which can be a big problem. In order to become activated, it needs to bind with its ligand, which I found also endearingly described as its soulmate, i.e., the above-mentioned CD40L (“L” stands for “ligand,” by the way), also known as CD154. So, as I understand it, the modified cold virus acts like a little Cupid reuniting two passionate lovers that are lethal to certain types of cancer cells. The embrace between CD40 and its ligand, in fact, sets off a cascade of events that eventually lead to the death of these particular malignant cells.

I should note that a body’s immune system becomes activated during this process. Now, a blog reader recently brought up the point that the immune systems of myeloma patients are already over-stimulated and should not be stimulated any further. I have read warnings to that effect here and there on Internet but have to confess that it is not a theme that I have researched thoroughly. I recognize that it is an important topic, though, so it will be added on my to-be-researched-in-a-hurry list.

CD40 and myeloma studies. There are heaps of ’em. I will discuss only a few of all the studies I have gone through since yesterday. A 2002 Dana Farber study published in Blood (see full text: http://tinyurl.com/249aog) tells us that CD40 induces MM cell migration and vascular endothelial growth factor (VEGF) secretion, suggesting a functional role of CD40 activation in MM homing and angiogenesis. This functional role is bad news for us, of course. When CD40 is activated, the researchers suggest, the result is tumour progression. CD40 also activates the infamous NF-kappaB, which, as we know, protects myeloma cells from death, via different mechanisms. In essence, CD40 appears to be involved in the proliferation of myeloma cells, so the authors suggest that targeting this pathway may prevent multiple myeloma from progressing. Interesting.

This had already been suggested back in 1995, again by a Dana Farber team (http://tinyurl.com/3b983v). Here are a few relevant excerpts from the 1995 “Blood” study: MM cells can be triggered via CD40L to secrete IL-6, suggesting the possibility for induction of IL-6-mediated autocrine MM cell growth. [ ] CD40L-CD40 interactions between MM cells, or between MM and BMSCs may be implicated in triggering IL-6 secretion and result in both paracrine and autocrine IL-6-mediated tumor cell proliferation. This study stopped me from looking fondly upon the modified cold virus theory. I am not sure what these “interactions” are, but perhaps it is not a good idea to put these two proteins together in the case of myeloma, unless I have totally missed the point or unless things have changed in the past 12 years, which is more than possible. The study ends: Further elucidation of the in vivo role of CD40-CD40L interactions between MM cells and cells within the marrow microenvironment may, not only elucidate the mechanisms of IL-6-mediated tumor cell growth, but also offer innovative therapeutic strategies. Indeed! The jury is still out.

Targeting CD40. Another Dana Farber study (full study: http://tinyurl.com/2fa4t5) published in 2005 discusses an anti-CD40 monoclonal antibody tested against multiple myeloma cells. This antibody, CHIR-12.12, apparently can inhibit multiple myeloma cell growth in the bone marrow milieu. I don’t need to underline the importance of THAT sentence! Two Phase I clinical trials are currently investigating the anti-CD40 theory in multiple myeloma. One is testing an anti-CD40 monoclonal antibody called SGN-40 (Anti-huCD40 mAb) on refractory or recurrent multiple myeloma (see: http://tinyurl.com/ysahre), in various medical centres throughout the U.S. This 2005 abstract provides information about SGN-40 and the above-mentioned trial: http://tinyurl.com/2wd567. SGN-40 apparently inhibits malignant cell growth by both antibody-induced cell death (AICD) and antibody-dependent cell-mediated cytotoxicity (ADCC). The other trial (http://tinyurl.com/2easoj) is testing HCD122, another anti-CD40 monoclonal antibody, on relapsed or non-respondent myeloma patients.

Speaking of clinical trials, the Birmingham researchers are in the process of developing skin and liver cancer clinical trials to test the above-discussed modified cold virus technique. I admit that I find all of these studies interesting, even though molecular science and fiddling around with genes is not my cup of chocolate and curcumin 😉 , and I doubt I would ever participate in an anti-CD40 myeloma clinical trial. But hey, the thought that curcumin or one of the other non toxic substances in my protocol might already target this protein just popped into my head. More research…tomorrow.

Saturday Smiles: The Wishing Floor, No Ice Cream, Tootles And Hopeless Wines

As a former professional translator who still occasionally translates, I enjoy funny translations. I recently came across a list of English signs found in non-English speaking countries. Amusing enough to give a boost to our NK cells? 🙂

In a Japanese hotel room: Please to bathe inside the tub.

In a Bucharest hotel lobby: The lift is being fixed for the next day. During that time we regret that you will be unbearable.

In a Belgrade hotel elevator: To move the cabin, push button for wishing floor. If the cabin should enter more persons, each one should press a number of wishing floor. Driving is then going alphabetically by national order.

In a hotel in Athens: Visitors are expected to complain at the office between the hours of 9 and 11 A.M. daily.

In a Japanese hotel: You are invited to take advantage of the chambermaid.

In the lobby of a Moscow hotel across from a Russian Orthodox monastery: You are welcome to visit the cemetery where famous Russian and Soviet composers, artists, and writers are buried daily except Thursday.

On the menu of a Swiss restaurant: Our wines leave you nothing to hope for. (One of my personal favourites! Hehe.)

In a Vienna hotel: In case of fire, do your utmost to alarm the hotel porter.

In a Rome laundry: Ladies, leave your clothes here and spend the afternoon having a good time.

Advertisement for donkey rides in Thailand: Would you like to ride on your own ass?

On the faucet in a Finnish washroom: To stop the drip, turn cock to right.

In a Swiss mountain inn: Special today — no ice cream. (Another favourite.)

In a Copenhagen airline ticket office: We take your bags and send them in all directions. (Ditto.)

In an Acapulco hotel: The manager has personally passed all the water served here.

From a brochure of a car rental firm in Tokyo: When passenger of foot heave in sight, tootle the horn. Trumpet him melodiously at first, but if he still obstacles your passage then tootle him with vigor.

Health Check Day and New Curcumin MD Anderson Article

I had to go to my doctor’s office yesterday because he wanted to have another look at me but was unable to make a house call. After listening to my wheezy chest, he insisted that I have an X-ray, so I had to go to the nearest radiology center to have that done. I will have the results this evening. Anyway, by the time we (my parents and I) got home, I was too pooped from the effort of driving (etc.) to write a post for my blog, as I had intended to do.

There is more health stuff. Since I was clearly not responding to the antibiotics I have been on since last Saturday, my doctor changed my course of treatment. So now my mother-in-law is giving me injections containing a different, stronger type of antibiotic twice a day (joy !), and I am also taking a different oral antibiotic. By now I must have more antibiotics than blood running through my veins! Well, the important thing is that the new type of antibiotics seem to be working, knock on wood. Since my dosage would probably have a positive effect on a sick animal the size of an African elephant, I feel weaker but am also coughing less violently this morning. Yes, I seem to have turned the corner. Finally. And my quirky dark sense of humour is back en force, always a good sign. It will be a long convalescence, though, apparently. Bummer. The bad news is that my parents (primary caregivers) are also ill. More or less with the same thing, even though they are not as ill as I have been. They may be forced to postpone their return trip to the U.S., though. I doubt they will be in shape to leave next Wednesday. Well, I would be happy to have them stay on, of course, but not for poor health reasons! Drat.

Since my parents and at least half of the residents of Florence are ill these days, I am feeling more upbeat about my brave little immune system. A friend of mine pointed out yesterday that all things considered I am doing quite well. She is right, of course! 🙂

On a brighter note. Yesterday that same dear friend sent me the link to a new MD Anderson article on curcumin. See: http://tinyurl.com/3d3xnn I was excited to read the news that a team of MD Anderson researchers is in the process of developing an intravenous, liposome-encapsulated delivery system for curcumin. Based on lab results, the researchers report that this system is very potent. I should mention that this is not the first time I have read about such delivery systems (see: http://tinyurl.com/2b699s, e.g., which discusses liposomal curcumin and head and neck squamous cell carcinoma cell lines), but the BIG news, in my view, is that the MD Anderson curcumin team hopes to schedule a Phase I liposomal curcumin clinical trial in 2008.

2008??? Why, that’s just a few months away! Patients with different types of cancer would be enrolled. Boy, if I lived closer to Texas, I would be very glad to participate in this clinical trial! The researchers, by the way, have filed a patent application for this particular delivery system, and those who are interested in reading more about it (it’s very long, so I haven’t read the entire application, yet) can go to: http://tinyurl.com/2qgt6z The curcumin research team also published an article in the April 2007 issue of Molecular Cancer Therapeutics, discussing the growth inhibiting and apoptotic effects of liposomal curcumin on colorectal cancer in vitro and in vivo. See: http://tinyurl.com/yv9f9x Anyway, I urge you to have a look at the above-mentioned article, which also gives the results of a study done with pancreatic cancer patients. Be well, everyone!

Parthenolide Analog-Blood Cancer Clinical Trial Soon To Begin In England

I have already posted about parthenolide, extracted from feverfew, a traditional daisy-like medicinal plant used mainly in the treatment of migraines. See my page on parthenolide on the right-hand side of my homepage for more details. I have been following this research for a while, now. And I finally have an interesting update. This morning I received a Google Alert concerning a parthenolide water-soluble analog called dimethylamino-parthenolide (or DMAPT for short), which swiftly kills leukemic stem cells (LSCs) from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-kB, and activation of p53. The compound has approximately 70% oral bioavailability [ ]. I took this from the abstract, which is publicly available at: http://tinyurl.com/2ytvoa

Thanks to a close friend (grazie!), I was lucky enough to get my hands on the full study, which was published in Blood on September 5, 2007. Here are a few of the more relevant excerpts. LSCs, the study tells us, are dormant and for that reason do not respond to chemotherapy, which targets only active cells. This is probably why relapses occur. Another problem with conventional leukaemia chemotherapy is that it is very toxic to normal stem cells. Not good.

Previous studies, the researchers point out, show that NF-κB, a known regulator of growth and survival, is constitutively active in LSCs but not in normal hematopoietic stem cells (HSCs). Notably, many traditional cancer therapies induce activation of NF-κB, a potentially undesirable characteristic likely to facilitate survival of malignant cells. Now, this is fascinating. I didn’t realize that some conventional chemotherapy actually ACTIVATES NF-κB! Gee whiz. That is not good at all.

The study also reports that it is not enough to inhibit NF-κB in order to induce apoptosis in acute myelogenous leukaemia. The tumor suppressor gene p53 needs to be activated, and oxidative stress must also be induced by boosting the levels of reactive oxygen species (ROS) to the point where the cell simply cannot survive any longer (as I understand it). The researchers report that their data suggest that the mechanism of LSC death involves combined inhibition of survival pathways and activation of tumor suppressor and/or stress pathways. They also discuss one of their previous findings, i.e., that the robust apoptosis of primary AML cells can be achieved with a single agent, the plant derived compound parthenolide (PTL), which is known to induce oxidative stress and inhibit NF-κB. Importantly, PTL also effectively eradicates AML stem and progenitor cells in vitro while sparing normal hematopoietic cells. So, parthenolide, or PTL for short, kills acute myelogenous leukemia cells (AML), including AML stem cells, but does not affect normal stem cells. I had actually already mentioned that (see my page), but it’s always good to repeat things, sometimes.

As we have seen happen with other compounds such as curcumin, though, PTL is poorly absorbable. So the researchers tested several PTL analogs, finally identifying DMAPT, which is over 1000 fold greater solubility in water relative to PTL. Wow! The study continues: DMAPT effectively eliminates human AML stem and progenitor cells without apparent harm to normal hematopoietic stem and progenitor cells. The compound also eradicates phenotypically primitive blast crisis CML and acute lymphoblastic leukemia (ALL) cells. Excellent.

The lab tests were performed using primary human AML, CML, ALL cells, and normal bone marrow (BM) cells. For those who are more scientifically-minded, DMAPT was prepared from the reaction of parthenolide with dimethylamine, and the resulting dimethylamino analog was then converted to its water-soluble fumarate salt.

DMAPT was found to induce the apoptosis of dormant leukemic stem cells as well as rapidly dividing active leukemic cells. This is important, of course. Researchers tested DMPAT also on three dogs with advanced CD34-positive spontaneous leukaemia. The dosage, 50-100 mg per kilo, was well tolerated, and the results showed obvious in vivo activity of DMPAT on the dogs’ leukaemic stem cells through inhibition of NF-κB and induction of oxidative stress.

The study ends by stating that Taken together, the data indicate that DMAPT mediates in vivo biological changes in leukemia cells that will lead to their impairment and/or death. Moreover, given the strong efficacy of the drug for AML stem and progenitor cells in vitro, we propose that a similar effect is possible in vivo, and provide preliminary evidence that LSC-specific targeting can occur in spontaneous canine leukemia. Based on these preclinical findings, its oral bioavailability, and a favorable toxicology profile, DMAPT is proceeding to human phase I clinical trials in the near future.

And in fact, according to a recent University of Rochester Medical Center news release (http://tinyurl.com/28l75m), clinical trials are set to begin in England before the end of the year. Oh, and by the way, DMAPT seems to have an effect on multiple myeloma cells, too, according to Monica Guzman, one of the main researchers. YIPPEE, I say!

Blog Reader Suggestions On How To Take Curcumin

Spoonful of curcuminToday I thought I would gather together a few more of my blog reader suggestions (if I have forgotten anyone, please let me know!), and also show a few photos documenting how I am currently taking curcumin (see explanation below). The curcumin powder here depicted (see photo on the left) is the C3 Complex curcumin, without bioperine, that I order from the Italian distributor for the Sabinsa Corporation. I keep it in a hermetically sealed ceramic jar so no air and light will make it deteriorate.

A blog reader with a plasmacytoma (diagnosed three years ago) is currently stable. He takes curcumin together with a product called Barley Green, which, from what I gathered on Internet, is composed mainly of organic barley grass containing active enzymes, minerals, B-vitamins, amino acids, essential fatty acids, carotenoids, bioflavonoids, and chlorophyll. This mix allegedly gives a boost to the immune system and reduces inflammation. I have never tried it, but I HAVE been curious to try wheatgrass, which is not readily available here in Italy, though. I love what this blog reader says about myeloma cells, i.e., that they don’t like green. When I visualize, I focus sometimes on things that my myeloma cells don’t like, and it makes sense that they don’t care for healthful diets full of green veggies. So this is interesting. Does anybody else here take a similar green product?

Another blog reader suggests letting curcumin rest in the flaxseed or liquid preparation for about a half hour before drinking it in order to give it time to go through and finish its chemical processes. This is analogous, I suppose, to letting fresh homemade pasta dough “rest” before rolling it out. An interesting idea. The only thing that would concern me is that curcumin is not happy when exposed to air and light. But perhaps mixed in a liquid would lessen its chances of losing any of its healthful properties. Any thoughts on this?Chocolate curcumin mixture

Blog reader number three dissolves curcumin powder in very warm milk and then adds the omega 3 oil from a capsule (Omega 3-6-9 lemon flavor from Nordic Natural). She says this makes it very palatable. When she mixed it with coconut milk (as yours truly used to do), she did not like it (neither did I). It was the smell from the milk what make her sick (no kidding! Me, too!). Sometimes she adds coconut oil to her concoction, which tastes very good, too, she reports.

A fourth blog reader does the following: I mix the caps of curcumin in a teaspoon or two of organic flax seed oil – it dissolves easily. Then I add about 1/3 cup of organic fruit yoghurt and stir it up. Next I add a 1/4 to 1/2 cup of frozen raspberries (or other small frozen fruit). Stirring this turns it into a kind of frozen yoghurt “ice cream” which doesn’t taste wonderful but is palatable due to the fruit flavour and the cold (which reduces the flavour). This is also an interesting method. I tried mixing curcumin powder in organic fruit yoghurt in the winter of 2006, between November and January 2007, and my IgG numbers didn’t decline at all. I just checked, though, and my monoclonal component did indeed decrease, which is important. So, that method might work after all, even though there is no heat involved (remember the abstract on increasing the bioavailability of curcumin by heating it up?). At any rate, in January 2007 I switched to curcumin capsules with bioperine, and my subsequent tests showed a decline in my IgG count, the first decline since November 2006, but also a slight increase in the monoclonal component. Sigh, this is SO hard to figure out.

What I actually drankHere are three not-so-great photos documenting my now daily chocolate curcumin preparation (two preparations/day). The photo at the top shows a full teaspoonful of curcumin, about four grams; the second photo shows four grams of curcumin powder sprinkled over the warm, almost hot, chocolate, butter and milk mixture, and the third shows what I actually drink, which is lighter in colour compared to the mixture in photo 2, obviously. The taste is not bad at all. And this is also not a bad way to get my chocolate hit for the day! 😉