Thursday, 5 January 2017

PLK1, IDH1, and Genistein

Came across this study on sensitizing IDH1 mutant tumors to TMZ.  Inhibiting PLK1 sensitized mutant IDH1 gliomas to TMZ in mice.  


They used the small molecule BI2536 which is not currently available outside of clinical trials.   However, I did find a 2016 study on Genistein (which is available retail) and its possible inhibition of PLK1.

 Sensitivity of TP53-Mutated Cancer Cells to the Phytoestrogen Genistein Is Associated with Direct Inhibition of Plk1 Activity.

Some more info on Genistein here as well.


  1. Whenever I read a study testing therapeutics in vitro ("in glass", in a test tube or dish or plate etc. as opposed to in a living body), my first question is always, "at what drug concentration"? In the genistein study, which I can upload to the Library if you wish, the concentration of genistein that inhibited 50% of PLK1 kinase activity was about 8 micromolar. 1 micromolar had very marginal activity and 5 micromolar inhibited about 30% of PLK1 kinase activity.

    After a single dose of 300 mg genistein you could expect a plasma maximum concentration of 2 micromolar of glucuronidated genistein and only 80 nM of unglucuronidated, or "free" genistein. That is to say, about 96% of the genistein in the plasma is conjugated with glucuronide. This is a process that occurs in the liver to prepare the "toxin", in this case genistein, for excretion. Whether or not glucuronidated genistein would have any PKL1 inhibiting activity at all is a big question not addressed by the study.

    If not, then with 80 nM of free genistein in the plasma, you've got about 8% of the minimum concentration of genistein that would have any noticeable activity at all aginst PLK1.

    But for brain tumors, the genistein needs to get into the brain. In the brain you'd likely get only a fraction of the free genistein that you'd find in the blood plasma.

    I'm sorry to say that much, perhaps a majority, of in vitro work has no clinical relevance whatsoever, because of the failure by the researchers to pay attention to pharmacokinetic concerns (ie how much of a drug, in active unbound form, is achievable in the target tissues in the body).

    1. Very true Stephen! However, for the more adventurous type, what about intrnasal administration or intravenous? Perhaps creating your own liposomes (which aids in absorption with lipid attachment and is not too difficult to do at home) before intranasal administration would solve the first-pass metabolism issue.

      I often think to myself that if I was diagnosed with GBM and was forced to use what herbs/supplements were available at retail, knowing the issue with first pass metabolism (i.e. curcumin) and BBB permeability, if I would not just concoct my own intranasal solution before administration. Of course there are risk in that and would want to start with a dose that is lower than recommended for oral delivery.

    2. Also some good studies about proper intranasal delivery would be worth taking a look at.

      Just a brief search and found this one for mice:

      "Results indicate that the brain uptake of intranasally delivered therapeutic(s) is > 5 times greater than that after intraperitoneal delivery."

      In this scenario if intranasal results in uptake >5 times that of a stomach injection then I would guess that intranasal would result in much greater than 5 times uptake if therapeutics were orally ingested.


      Yes indeed, there is a lot of potential in intranasal delivery and there deserves to be much more research into it than has been done to date.

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  3. Steve
    How can I access the library ?
    Thank you for all you do

    1. Hi Robert,
      I just need your email address to share the Library with you. My email address is on the User Information page, at the top of the blog.