This is a very important topic to understand. I have learned much from the linked article’s references showing the inter relationship between the loss of the zing transporter ZIP1 in prostate cancer, and then the contributing effects of testosterone and of prolactin in maintaining and progression to testosterone independent CRPC and prolactin dependent then independent PC. The following study explains the whole dilemma. You can skip to page 24 if you find the mechanisms confusing.
ncbi.nlm.nih.gov/labs/pmc/a...?
report=reader
The implications for treatment include adding a ZIP1 independent means for restoring zinc levels that are toxic to PC cells. Clioquinol is a zinc ionophore proposed for this purpose. Clioquinol is available as a 3% topical product (Vioform and others). So applying some amount to skin in some amount or frequency while also supplementing zinc 30-50 mg may have some therapeutic value. However I am not aware of any clinical trials on this and am unclear about Clioquinol bio availability via the skin, or how much to apply. Quercetin also has zinc ionophore activity.
ncbi.nlm.nih.gov/labs/pmc/a...
Then there is the other issue of prolactin also being a regulator of PC progression, especially during androgen ablative treatments, ADT. A good case is made for the possible therapeutic role of Cabergoline to suppress prolactin on the way towards androgen independent PC. What was not clear to me is the timing. The original article posted seems to suggest that prolactin suppression is most important after castrate resistance has occurred. But the mechanisms layer out in the first article above imply that prolactin suppression should be employed as soon as ADT is started as a long-term treatment.
I will also post this in a new thread to collect more thoughts on it. Thank you RISH1.
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MateoBeach
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I started my husband on Quercetin and Ionic Zinc at the same time he started Abiraterone and his PSA and T doubled in 2 months instead of declining with Zytiga.after much research, I found out that Quercetin "might" interfere with the excretion of T:
supplementsinreview.com/tes... October 15, 2017
“Decreasing T excretion: Early research suggests that quercetin reduces the activity of an enzyme needed to remove testosterone from the body through urine. UGT2B17 is an enzyme that converts testosterone into testosterone glucuronide – the form in which it can be excreted out of the body through urine. This has the effect of lowering your circulating testosterone levels. Quercetin has been shown to inhibit this enzyme’s activity by as much as 72% in isolated cell culture, meaning that the excretion of testosterone is slowed down, and its circulating levels are increased.
In addition, there is early research evidence that quercetin can protect the prostate and testes and even boost testosterone levels, especially in the context of health disorders such as diabetes. Because of this, it is sometimes included as an ingredient in testosterone booster formulas.”
He stopped taking the Quercetin and 3 weeks later his PSA went from 0.93 to 0.17
Coincidence? Maybe. However, I think it was the Quercetin: If Zytiga keeps T from binding to cancer cells, the T is floating around; if the enzyme needed to convert it for excretion is hindered, then T is going to be higher
Hubby's PSA is now 0.06 YIPEE!! but his T keeps creeping up; after stopping Quercetin, T was still higher than before--37, had been 24. Now up to 54 even though PSA dropped to undetectable. I am thinking it's the Zinc drops since I just read that zinc can/does increase testosterone levels. Thoughts??
You cannot compare to these effects either in cell culture nor in humans that are not being treated with ADT and abiraterone. Those effectively block production of testosterone if adequately present. The very low PSA suggests it is still hormone sensitive and thus not rising while on this regimen. Testosterone secretion limitation by Quercetin should be a non issue in principle. Abiraterone blocks all testosterone synthesis everywhere: in testes, in adrenals and in PC tumors (until androgen independence finally develops). Is he on the full 1000 mg dosing?
thanks--yes, on full 1000 (two 500mg tablets together) per day plus 10mg Prednisone. He is also on Eligard once every 3 months. He started the Abiraterone in Sept after some bloodwork was done--it was between Eligard shots. That same day he started the Abiraterone, he started Quercetin and Ionic Zinc (10 drops)
2 months (Nov) later before Eligard, PSA shot up from 0.51 to 0.93; stopped Q and PSA went down 1 month later (Dec) to 0.17; now just before Eligard, PSA down even more to 0.06
T went from 26 (before Aug Eligard) to 24 in Sept, then jumped to 37 in Nov. It wasn't done in Dec bloodwork but is up to 54 now.
My thought was that since ADT + Abiraterone should block ALL T, then something had to make T go up after starting it--answer had to be Quercetin and/or Zinc. Zinc can increase T levels.
now for another fly in the ointment: Genome results (test FINALLY done in December) from biopsied tissue shows complete PTEN loss; this leads to increased activation of the PI3K-AKT-mTOR pathway (bad thing).
Since this test was done on biopsied tissue before any treatment started, I think he needs a liquid biopsy genome test to see what, if any, changes have occurred due to treatment.
The Quercetin conundrum:
1-Quercetin reduces the activity of the enzyme (UGT2B17), meaning that the excretion of testosterone is slowed down and its circulating levels are increased. HOWEVER, IF Zytiga STOPS/blocks production of T by inhibiting CPY17A1, is there any T to be converted by UGT2B17 and to be excreted??? IF NOT, then Q should not be an issue
2-BUT IF Q inhibits CYP3A4 (enzyme that metabolizes Zytiga), then does it keep Zytiga from stopping T production? IF so, then there is circulating T and Q IS an issue
3-Co-administration of quercetin and paclitaxel on prostate cancer cells has remarkably suppressed cell proliferation, increased apoptosis. The combination of quercetin and docetaxel has remarkably suppressed PI3K/Akt axis and enhanced apoptosis
SO, can Quercetin suppress PI3K-AKT-mTOR pathway alone or only with docetaxel?
Seems Quercetin would be good unless it keeps T production from being stopped; then it isn't.
Conundrum indeed. But as to #2, if Q inhibits CYP3A4 then it’s metabolism / breakdown is inhibited and levels of abiraterone should be higher. Seems that is not a problem unless the metabolites are the more active molecule?Sorry to learn of PTEN loss mutation. Another unwanted factor. There are mTOR inhibitors, but not proven in PC. I seem to remember something about Q down regulating PI3K-AKT-mTOR but need to recheck that. BTW admire your clarity of thought in your analysis. 👍🙏
Summary of metabolite activities, a mixed bag. From Wiki
Abiraterone, the active metabolite of abiraterone acetate, inhibits CYP17A1, which manifests as two enzymes, 17α-hydroxylase (IC50 = 2.5 nM) and 17,20-lyase (IC50 = 15 nM) (approximately 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase)[22][23] that are expressed in testicular, adrenal, and prostatic tumor tissues. CYP17A1 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity.[24] DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17A1 activity by abiraterone acetate thus decreases circulating levels of androgens such as DHEA, testosterone, and dihydrotestosterone (DHT). Abiraterone acetate, via abiraterone, has the capacity to lower circulating testosterone levels to less than 1 ng/dL (i.e., undetectable) when added to castration.[22][25] These concentrations are considerably lower than those achieved by castration alone (~20 ng/dL).[25] The addition of abiraterone acetate to castration was found to reduce levels of DHT by 85%, DHEA by 97 to 98%, and androstenedione by 77 to 78% relative to castration alone.[25] In accordance with its antiandrogenic action, abiraterone acetate decreases the weights of the prostate gland, seminal vesicles, and testes.[26]
Abiraterone also acts as a partial antagonist of the androgen receptor (AR), and as an inhibitor of the enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD), CYP11B1 (steroid 11β-hydroxylase), CYP21A2 (Steroid 21-hydroxylase), and other CYP450s (e.g., CYP1A2, CYP2C9, and CYP3A4).[19][27][28][29] In addition to abiraterone itself, part of the activity of the drug has been found to be due to a more potent active metabolite, δ4-abiraterone (D4A), which is formed from abiraterone by 3β-HSD.[30] D4A is an inhibitor of CYP17A1, 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase, and 5α-reductase, and has also been found to act as a competitive antagonist of the AR reportedly comparable to the potent antagonist enzalutamide.[30] However, the initial 5α-reduced metabolite of D4A, 3-keto-5α-abiraterone, is an agonist of the AR, and promotes prostate cancer progression.[31] Its formation can be blocked by the coadministration of dutasteride, a potent and selective 5α-reductase inhibitor.[31]
thanks for that reference--I had seen that along with "1000" others but I don't really copy and use much unless it's only 2-3 years old--so many thoughts and guesses have changed over time and what was once thought to be true may not be any more with improvements in testing and research and trials. But I appreciate it none the less.
Zytiga blocks the enzyme needed to generate T. Xtandi blocks the androgen receptors. I think it's unwise to take supplements during treatments due to the simple fact we don't understand all of the interactions. Nice to see your husband is responding well to ADT and zytiga. A good amount of aerobic and weights are just as beneficial as supplements...probably more so IMHO and the few studies showing increased os and qol.
Important disclosure I did not include in the post:None of these topics or potential therapeutics is SOC and I am not recommending them for anyone. Efficacy for treatment has not been tested in randomized prospective clinical trials, RCTs, to my knowledge. This is for informational purposes only.
The 1/31/2019 MRI and PET revealed the absence of detectable malignancy. A CTCPC (circulating tumor prostate cells count) count = 5.4 on 8/27/2018, which is indicative of ~21 months of survival; and on 2/22/2019, the count=0. This reveals that the imminent death from androgen-independent metastases had been terminated.
Professor Costello makes a compelling theoretical case for zinc+ionophore, and a prolactin inhibitor. However, as RSH1 writes, there is little in the way of clinical trials and unfortunately no other researchers have taken up the tack.
I was in contact with prof Costello who on his own initiative generously sent me clioquinol that I couldn´t get hold of without a prescription, and I started the treatments. Later he wanted to use my case history as his second case. I was a bit taken back since my no evidence of disease could have been because of ADT or other supplements and he didn´t seem to be concerned about this.
Anyway, it just might work, who knows. Zinc might be good to take anyway and there are slightly more indications for benefit of prolactin inhibition. Long-term use of hydrocortion, that is included with the clioquinol, poses an increased risk for infections. So I started with chronic, zinc ionophore (low-dose) quercetin instead, which might have other benefits anyway. Now came the post from KAgolf about a possible down-side to quercetin... this ain´t easy.
PS This study, with 1000 mg Quercetin daily for 8 weeks for 40 adult males, shows no difference in serum testosterone levels before and after. ncbi.nlm.nih.gov/pmc/articl...
I will continue with my little insurance per Costello´s protocol. Just in case.
It’s my understanding that prolactin, FSH, and LH all primate angiogenesis. It would seem that elevation of any of these is not desirable with prostate cancer or other neoplasms.
Hello MateoBeach, disulfuram (DSF), or antabuse, is a zinc ionophore as well. I trialed 250 and 500 mg of DSF + 50 mg of zinc for a month and it had no apparent effect on the PSA trend (i.e., no slope change). There is a good theoretical basis for an ionophore and zinc combination, but there have been no clinical trials to demonstrate efficacy, perhaps because drug companies see no profit in it. It would be interesting test an ionophore + Zn and Zn alone as part of a BAT trial - it may show efficacy in this setting IMO. Cheers, Phil
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Has anybody been prescribed Clioquinol
My Last Post Regarding Clioquinol for Virus's, and PCA
ADT enhances the immune system
