Genistein and signalling pathways

Yesterday I went through the 2006 “International Journal of Cancer” study (abstract: http://tinyurl.com/7eady3), which discusses how genistein affects the transcription factor NF-kappaB and the Notch-1 signalling pathway in pancreatic cancer cells.

 

[Note 1: Notch signalling is crucial for the growth and survival of multiple myeloma cells, not just pancreatic cancer cells…see, for instance, these two “Blood” 2004 abstracts: http://tinyurl.com/9p7k5e and http://tinyurl.com/7f9vzw. So this discussion is relevant to us myeloma folks, too.]

 

The abstract informs us that Notch signalling helps maintain the balance between cell proliferation, differentiation and apoptosis, and thereby may contribute to the development of pancreatic cancer…this process is, however, blocked by genistein. And, by inhibiting Notch-1, genistein also blocks NF-kappaB, which mediates survival signals that inhibit apoptosis and promote cancer cell growth. This process also affects the genes controlled by NF-kappaB, as we will see in a sec.

 

The cancer cells have no way out…except death.

 

[Note 2: the implications of inhibiting the Notch/NF-kappaB signalling process gave another push to my idea of gathering in one place (say, an Excel spreadsheet) all the data I have collected in the past year or so…if only I had more free time, had a scientifically-oriented brain, and were more organized…eh. Well, my rambling all over the place will simply have to do for now. But I have to admit that even I get overwhelmed by all the info contained in my own blog!!! If I could condense it somehow…]

 

The full study begins with the usual cancer statistics…in this case, of course, those concerning pancreatic cancer, which has the worst prognosis among all major cancers. Apparently, though, people whose diets are high in soy are less likely to get this type of cancer, suggesting that a high intake of soy products may protect people against pancreatic cancer.

 

Basically, as anticipated in the abstract, the study demonstrates that the inhibition of Notch-1 blocks NF-kappaB, at least in part. And this process also hinders genes that are regulated by NF-kappaB, such as COX-2, cyclin D1, MMP-9, Bcl-2, Bcl-xL and survivin. Well, well, we meet again…these are all genes implicated in the survival and merrymaking of myeloma cells, so this is a very important point.

 

In conclusion, the study demonstrates that the administration of genistein leads to the death of pancreatic cancer cells. The researchers speculate that one possible mechanism by which genistein induces apoptosis is due to down-regulation of Notch-1, a gene that is abnormally activated in many human malignancies and keeps pancreatic cancer cells alive and well, as it does with other types of cancer cells (erythroleukemia and cervical cancer are mentioned here).

 

And, as we know from my December 29 post, genistein also kills myeloma cells AND increases bone formation…

 

Toxicity issues. I was actually somewhat reassured after perusing a report carried out by the National Toxicology Program (U.S. Dept of Health and Human Services) in 2006, see http://tinyurl.com/9voc22 Incidentally, it answers Chris’ question concerning chickpeas. Even though the main source of genistein is soy, much smaller amounts can also be found in Lentils, peas, kidney beans, peanuts, chickpeas, broccoli, cauliflower, and barley meal. The report concludes that genistein is safe for human (adult) consumption. In order to reach possibly harmful levels of genistein, we would have to swallow huge quantities of the stuff, more than 35 mg/kg a day. Yep, that’s a lot. In any event, the main potential toxicity has to do with reproductive issues, which is not a concern for me.

 

I also took a look at a more recent (=2008) NTP report (see: http://tinyurl.com/7z3gnd) that confirms that although genistein did show adverse effects with dietary exposures of 100 or 500 ppm, there were no clear adverse effects on the reproductive or developmental parameters measured at genistein concentrations ranging from less than 1 ppm (control diet) to 100 ppm, a range of doses producing serum concentrations achievable from the phytoestrogen content of human diets.

 

Well, the more I read, the more I am tempted to try genistein (only from a certified non-GMO source), but I have other things to test first…in the meantime, I will (try to) keep an eye on this substance, too…

4 Comments

  1. Hi Margaret, This is my normal supper since the beginning of August last.
    The Garlic sandwich.

    2 slices of organic wholemeal bread
    Spread one slice generously with miso (the dark variety)
    3 or 4 garlic cloves depending on size, sliced and spread over it.
    Drizzle the other with hemp seed oil (sold by Sainsbury as
    “The Good Oil”), otherwise flax oil,otherwise pumpkin oil,otherwise
    good old extra virgin olive oil (Italian of course).
    Sprinkle generously with turmeric and 4 or 5 twists of
    freshly ground black peppercorns.
    The garlic must be raw.
    Chew each bite at least 30 times then swallow.

    That’s it except to say I feel better that before August,
    now perhaps I know why.
    Many thanks once again.(and again and again).

    Old Bill

  2. My numbers had gone down but now seem to be turning around and may be going up again. M-spike was 1.0 for a few cycles and Thursday it was 1.1. Could be an anomaly, but I rather doubt it.

    I’m getting more and more interested in genistein. I’ve tried everything else, including curcumin, resveratrol, quercetin and more. I’m becoming convinced that none of those things is helping, even the curcumin, so I’m on the lookout for a new supplement regimen.

    Thanks for all that you do! Take care, Don

  3. Hi Good work Margaret, you have a knack for pulling out all the relevant juicy bit of info.

    On a more sombre note as I read your post I thought of Patrick Swayse, who I heard today has been hospitalised with pneumonia following chemo for his pancreatic cancer. I have been praying for him and thought perhaps we could all spare a thought for his recovery

    wishing you the best of health

    Sue

  4. Dear Margaret:

    Recently, a solid lipid nanoparticle formulation of curcumin has become available.

    The formulation was developed in the labs of two professors at UCLA:

    Professor Sally A. Frautschy http://alzheimer.neurology.ucla.edu/Frautschy.html
    Professor Greg M. Cole http://alzheimer.neurology.ucla.edu/Cole.html

    This formulation is described in detail in a patent application, PCT/US07/05829 (WO/2007/103435) http://tinyurl.com/3eaegw
    Bioavailable Curcuminoid Formulations for Treating Alzheimer’s Disease and Other Age-Related Disorders.

    The Regents of the University of California http://tinyurl.com/2bztov have licensed it to:

    Verdure Sciences, Inc.
    1250 East Conner Street
    Noblesville, IN 46060
    info@vs-corp.com

    This formulation has eleven times greater bioavailabiity in the plasma when tested in rodents (see note 1).

    Verdure has trademarked this formulation as Curcuminol M3Cx and Longvida. It is available in 500 mg capsules, and these may be obtained by contacting Blake Ebersole @ 317-219-0355 at Verdure. E-mail bebersole@vs-corp.com You can ask him to fax the forms a customer needs to fill-out to obtain the capsules. It is sold in packages of 100 capsules for $59.99. A 400 capsule package is available, too.

    Although curcumin has been given in clinical trials in doses as high as 12 grams a day with only minimal toxicity (note 2), I would reason that 4 grams (8 x 500 mg capsules) might be the optimal dose.

    Pharmanza Herbals Pvt. Limited, which is Verdure’s production facility in India, http://www.verduresciences.de/index.php?nav=2&lang=en, is acting as the sponsor for a trial of this curcumin formulation for advanced osteosarcoma at:

    Tata Memorial Hospital
    Advanced Centre for Treatment, Research and Education in Cancer (ACTREC)
    Pilot Study of Curcumin Formulation and Ashwagandha Extract in Advanced Osteosarcoma (OSCAT)
    http://clinicaltrials.gov/ct2/show/NCT00689195
    Manish Agarwal, M.D. 011-91-22-2417-7184 mgagarwal@gmail.com
    Vikram S. Gota, M.D. 011-91-22-2417-7000 ext 4537 vikramgota@gmail.com

    I spoke with Dr. Gota in July who told me that this formulation seemed effective in the early results from the trial. They are using a 4 gram/day dose.

    Regards,

    David Corbin

    REFERENCES

    1) Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease.
    Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA.
    J Pharmacol Exp Ther. 2008 Jul,326(1):196-208.
    http://pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18417733

    2) Dose escalation of a curcuminoid formulation.
    Lao CD, Ruffin MT 4th, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE.
    BMC Complement Altern Med. 2006 Mar 17,6:10.
    http://pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16545122

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