Indomethacin / Xtandi

My guess is that some out there are up to speed on indomethacin, but I don't recall reading about it before this morning.

[1] Wikipedia.

"indomethacin ... is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms.

"It is marketed under more than twelve different trade names. As of 2015 the cost for a typical month of medication in the United States is less than 25 USD."

Indomethacin is a non-selective COX inhibitor.

[2] (2016 - U.S.) From the preamble (translation below):

"Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3."

Translation: Resistance to Xtandi ultimately occurs. One of the escape pathways involves the synthesis to androgens via AKR1C3. Indomethacin inhibits AKR1C3.

This study investigated NSAID analogs with the same property, but without the COX-1 inhibition that can lead to peptic ulcers.

"R-Profens are ... selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease"

[3] (2015 - U.S.)

"The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer. However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide-resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene-expression analysis showed that the steroid biosynthesis pathway is activated in enzalutamide-resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide-resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide-resistant prostate xenograft tumors. LC/MS analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly upregulated in enzalutamide-resistant prostate cancer cells compared to the parental cells. Knockdown of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide-resistant prostate cancer cells to enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance; targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients."





5 Replies

  • Patrick,

    Thanks for all the good research. Did you come across any other compounds that inhibit AKR1C3. Could this explain the action of celebrex or even 5 Loxin. Maybe even motrin would have an effect.


  • Gus,

    My main interest has been in otc products.

    Caffeic Acid Phenethyl Ester (CAPE) has inhibitory properties [1].

    It is found in bee propolis. Sadly, most products have none & the best option isn't exactly cheap: (I use the capsules) [2]

    Berberine [3]





  • Patrick,

    Did you check out the link to the clinical trial on the topical estrogen cream on this blog. The authors are comparing its action to DES.



    Does this say something different ?

    Thanks Patrick



  • Els,

    From your link:

    "These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC ... patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth."

    The study I cited says that: "AKR1C3 is implicated in drug resistance".

    I have no idea regarding the percentage of men affected by AKR1C3. A significant number? or a "small subpopulation"? In either case, there will be men who benefit from an inhibitor.


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