Parthenolide and myeloma news

An aunt and uncle of Stefano’s spent the Xmas 2007 holiday with us. One day I told Stefano’s plant-loving aunt about parthenolide, or PTL, the active myeloma-cell-killing ingredient in the feverfew plant. my feverfew plantShe recognized the Latin name of feverfew (Tanacetum parthenium) and gasped: “But my mother has this plant growing WILD in her back yard!” Oh, you can imagine my delight at this bit of news! She promised to dig up and send me a bit of this plant as soon as spring arrived. So I now have a pretty little feverfew plant in my front yard (see the photo I took this morning). Now, I am not sure what I will be doing with it (preparing teas, perhaps? The highest concentrations of PTL, I read, are in the flowers and fruit of feverfew) but at the very least I am sure it will bring me good luck.

 

I used this little story and my photo as an introduction to today’s post about a recent U.S. study on the anti-myeloma effects of partenolide. I have already posted about two previous studies on the same topic–one Chinese, the other Japanese. For background info, please see my Page on parthenolide/DMAPT.

 

A blogging friend (thank you!!!) sent me the full text of this Indiana University School of Medicine study published in Clinical Cancer Research on March 15th 2008. In the abstract (http://tinyurl.com/5xxsu5) we can read that PTL has multifaceted antitumor effects toward both MM cells and the bone marrow microenvironment. Excellent starting point, I’d say! Okay, with no further ado, I will plunge right into the study.

 

The beginning of the full study has some interesting wording: Despite intensive chemotherapy, multiple myeloma (MM) remains an incurable, yet chronic, blood cancer with over 14,000 patients diagnosed and 45,000 patients treated yearly in the United States The interaction of MM cells with the bone marrow microenvironment contributes to the heterogeneous treatment response and drug resistance.. Incurable, yet chronic, did you notice that? Hmmm, I think this may be the first study I have looked at so far that mentions the adjective “chronic” in the same breath as “myeloma.” Well, well.

 

Reading on, when myeloma cells adhere to the bone marrow stromal cells (BMSC), that is, to the cells and the supporting tissue that surround the myeloma cells in our bone marrow, NF-kappaB activation in the BMSCs up-regulates interleukin-6 (IL-6) and vascular endothelial growth factors, which further enhance MM cell growth both directly and, in the case of vascular endothelial growth factor, also indirectly via promoting angiogenesis. Vascular endothelial growth factor is abbreviated as VEGF and, in a nutshell, is a tumour-feeder.

 

The researchers identify NF-kappaB as the main culprit in the myeloma proliferation process, since it affects both the tumor cells and the supporting microenvironment.

 

And it just so happens that parthenolide inhibits NF-kappaB (as do curcumin and practically every substance that I have researched and posted about here!). Its anti-tumour effects have been observed in various cancers, including breast, lung, prostate, cholangiocarcinoma, and acute myeloid leukemia. It also increases the effectiveness of chemotherapy, which might be of interest to those who are doing chemo right now.

Interesting titbit: one of the anti-myeloma strategies criticized by the Indiana researchers is the use of Bortezomib (Velcade), in this sense: the proteosomal inhibition in normal cells can lead to significant side effects due to the accumulation of toxins, which would otherwise be removed by a fully functional proteosome. The Indiana researchers argue that targeting NF-kappaB might instead lower toxicities while maintaining efficacy. Hmmm.

At any rate, the researchers tested parthenolide in myeloma cell lines that had become resistant to dexamethasone and doxorubicin. After 72 hours, PTL inhibited the proliferation of these resistant cells.

 

Now, since I know a few myeloma folks who are taking dexamethasone, here is some info on PTL used with dex. The researchers found out that this combination is synergistic.

Here is the gist: Parthenolide activates both the extrinsic and intrinsic apoptotic pathways, whereas other anti-MM treatments, including conventional chemotherapy, radiation, and glucocorticoid, primarily activate the intrinsic apoptotic pathway. We hypothesize that simultaneous activation of both apoptotic pathways may enhance cytotoxicity. Our finding of an additive cytotoxicity with the parthenolide and dexamethasone combination supports this concept.

 

Oh, you may ask what “extrinsic” versus “intrinsic” apoptotic pathway means? Good question. Not easy to answer, but basically the death of a cancer cell can be caused by “die, you scoundrel!!!” signals transmitted by so-called “death receptors” located on the cell’s surface, that is, external (to the cell) signals, or by death signals that originate inside the cell such as those deriving from DNA damage or from chemotherapy.

The researchers also found that PTL is toxic only to myeloma cells, not to the surrounding healthy ones. Now, haven’t I read that BEFORE?

Parthenolide also attenuated the protective effect of the bone marrow microenvironment on myeloma cells. And IL-6 was unable to protect the myeloma cells from the toxic effect of this powerful plant extract. For the scientifically-minded: Parthenolide inhibited the NF-kappaB–DNA binding and further reversed the effect of TNF-alpha–induced NF-nB activation.

The study concludes that parthenolide is effective against MM cells in the context of the bone marrow microenvironment and that its mechanisms of action are both caspase-dependent and independent. In combined therapy, parthenolide is additive and synergistic with dexamethasone and TRAIL, respectively. Our findings provide a rationale for the clinical development of parthenolide. (TRAIL, by the way, stands for TNF-related apoptosis-inducing ligand; basically, it helps induce apoptosis in cancer cells.)

How about that?

9 Comments

  1. This is really great news! You get the best information – thanks so much for finding this! I am excited: Velcade didn’t work for me, and neither does Dex. Maybe parthenolide would open the door for a different chemo…or maybe it would help the Velcade work (I will never take dex again). Do you know if it is available yet in clinical trials, or do you get it over the counter? I will have to read the study, but thanks so much for cluing me into this!

    Lisa

  2. Hi Lisa, you can check http://www.clinicaltrials.gov for all ongoing trials. I just did (again), and yes, parthenolide is being tested, but only in a contact dermatitis trial at the moment. Not very helpful to us, eh!
    However, its analogue, DMAPT, is going to be tested on leukemic patients soon (?) in the UK in a Phase I trial. DMAPT kills leukemic stem cells in vitro, which is very very exciting!
    I am going to go ahead and give parthenolide a whirl. I found a product that has a 3% content of parthenolide (600 mcg) from feverfew leaves and will probably test it this summer. Unless something weird happens, I will test it for at least 3 months.
    Good luck with everything!
    🙂 Margaret

  3. Hi, Margaret,
    First – to make you smile: feverfew in Russian is called Girly Daisy!
    Its primary use is to treat migrane but hey, people used to eat boiled tea leaves and throw away the water:)
    Anyway, big question is, what to do with it. We are too late to plant it this year but there are dried leaves sold in the pharmacies. Make tea? it shouldn’t taste far off chamomile:)

  4. ciao margaret,
    i am reading your log since march. i have since 04 a simelar b-cell desease called malt lymphoma.
    i am drinking quasi each eavning my feverfew tea since feb 08 and got following experience:
    1) very bitter but you sleep very well; seditativ
    2) i am using dried and fresh plants. the dried plants i grate it in mixer or in a electric coffee grate machine to a pulver. than i sieve it and mix the pulver with hot water.
    THE PARTHENOLIDE ARE NOT WATER SOLUBLE, YOU HAVE TO USE
    THE WHOLE PLANT IN THE TEA.
    you can also extract the parthenolids with ethanol (wodka), but the disadvantage is than you are producing alcohol dehydrogenase and acetyl dehydrogenase. not good for variose things.
    i take also boswellia serrata 600 mg a day.
    sono austiaco e ho studiato un mese a trieste italiano.
    a presto
    roberto

  5. roberto: interesting approach but as you say that parthenolides are not water soluble how would putting the whole plant in tea change that? I would guess the parthenolides would not dissolve and there would be no uptake into either the lymphatic or blood system whatsoever. To my understanding this is what the whole DMATP story was about – water solubility is just not an option.

    at grouppe kurosawa this topic has been blogged on over many months and doc steve there proposes two solutions:
    – dissolve the parthenolides in fat and allow uptake via the lymphatic system
    – use dmso gel and pure parthenolide as a skin gel for uptake directly into the blood stream but for this one would need a source for pure parthenolide from a reputable source which works according to highest health standard – for private consumers I fear no such source exists.

    @ margaret: I only heard of 0.7% parthenolide content so far. Could you let us know how the 3% is called (I can also order directly from US)

  6. Ben, you are right about DMAPT, the PTL analogue that is water-soluble as opposed to regular PTL. But I wonder if using parts of the whole plant, as Roberto suggests, might provide other benefits. After all, that is how it was used in the past (and probably still is!) by so-called “folk” medicine. The problem is that we will probably never see feverfew tea tested in a clinical trial…right? Therefore, since DMAPT is not available to us (yet), I think it might be worth a try. I use the conditional tense, of course! 🙂

    Another thing. I agree with you that the DMSO gel method is a bit tricky to say the least. We have to be super-careful about injecting stuff directly into our bloodstream. Do we really know what the consequences would be?

    In my perhaps overly cautious view, this method is too dangerous, especially for folks who are not medically trained. Some time ago, a blog reader experimented with a topical application of curcumin (C3 Complex) mixed in some DMSO but stopped because he became concerned about solid crystals entering his bloodstream. I agreed with him.

    As for the 600 mcg PTL product I ordered, it’s called Mygrafew and is manufactured by Nature’s Way. I just had a closer look at the label (available on the Vitacost website) and am not sure if that 3 % refers to the feverfew leaf content or the PTL content. The syntax is a tad ambiguous. Regardless, it was the best thing I could find at the time, and it will have to do for now, until I find something better.

    Cheers, everyone!
    🙂 Margaret

  7. Ciao a tutti,
    Margaret is right, im drinking also the fine powder with the tea.
    The sesquiterpenlacton PTL methabolize simelar to carotinoides that are tetraterpene.
    You can also extract the PTL with ethanol.
    1 ml of ethanol can solve 20mg PTL.

    I found also an interesting link for a helpful lacton in a plant named
    Artemisia annua. You will found this plant quasi everywhere around vienna.
    “Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia”
    http://www.ncbi.nlm.nih.gov/pubmed/16075280?dopt=Abstract
    Photo of the plant
    http://upload.wikimedia.org/wikipedia/commons/thumb/d/db/.jpeg/300px-Artemisia_annua.jpeg

    Forse e utile per te. 🙂
    a presto
    roberto

  8. Hello from Tennesse,
    Margaret, how many capsules of the Mygrafew do you take a day? I am starting ny 5th year of having MM. Thank you.

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