Androgen Receptor [AR] Degradation.

[pjoshea13]

Ralph1966 has recently posted someting on DpC. To date, AR-axis targeted therapies have involved the denial of androgen to AR, competitive binding to AR, but not AR degradation. DpC does that.

But the subject of AR degradation goes back at least 20 years. The sublect interested me since some the studies involved phytonutrients.

[1] (2008): Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway

[1a] Wiki: "Traditional milk thistle extract is made from the seeds, which contain approximately 4–6% silymarin. The extract consists of about 65–80% silymarin (a flavonolignan complex) and 20–35% fatty acids, including linoleic acid. Silymarin is a complex mixture of polyphenolic molecules, including seven closely related flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, silydianin) and one flavonoid (taxifolin)."

[2] (2008): "Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and xenografts"

"Luteolin reduced the association between AR and heat-shock protein 90, causing AR degradation through a proteasome-mediated pathway in a ligand-independent manner. Luteolin also suppressed LNCaP xenograft tumor growth in SCID mice."

[3] (2009): "Novel anti-prostate cancer curcumin analogues that enhance androgen receptor degradation activity"

[4] (2011): "Curcumin provides potential protection against the activation of hypoxia and prolyl 4-hydroxylase inhibitors on prostate-specific antigen expression in human prostate carcinoma cells"

"Curcumin, a yellow curry pigment, has been reported to enhance androgen receptor (AR) degradation."

"curcumin treatment (10 μM) decreased the protein abundance of AR"

[5] (2016): Carnosic acid promotes degradation of the androgen receptor and is regulated by the unfolded protein response pathway in vitro and in vivo

[5a] Wiki: "Carnosic acid is a natural benzenediol abietane diterpene found in rosemary (Rosmarinus officinalis) and common sage (Salvia officinalis). Dried leaves of rosemary or sage contain 1.5 to 2.5% carnosic acid."

[6] (2016) Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

"Nutraceuticals that target AR signaling (epigallocatechin gallate [EGCG], curcumin, and 5α-reductase inhibitors), AR synthesis (ericifolin, capsaicin and others) or AR degradation (betulinic acid, di-indolyl diamine, sulphoraphane, silibinin and others) are prime candidates for use as adjuvant or mono-therapies."

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/183...

[1a] en.wikipedia.org/wiki/Silyb...

[2] pubmed.ncbi.nlm.nih.gov/180...

[3] pubmed.ncbi.nlm.nih.gov/196...

[4] pubmed.ncbi.nlm.nih.gov/219...

[5] pubmed.ncbi.nlm.nih.gov/272...

[5a] en.wikipedia.org/wiki/Carno...

[6] pubmed.ncbi.nlm.nih.gov/273...

[PhilipSZacarias]

An important issue. Perhaps resveratrol and artemisinin could be added to the list? In your opinion Patrick, which of the phytochemicals listed do you find potentially the most efficacious? Cheers, Phil

[pjoshea13 in reply to PhilipSZacarias]

Phil,

I'm an n=1 study with too many variables - number of supplements, combinations, doses, etc.). I'm driven to some extent by the number of studies, so curcumin is up there. Also when Pharma is testing analogs (curcumin again). I'm high on a couple of neglected pytochemicals - apigenin & fisetin. Captain_Dave's quercetin is a good one. Who knew that onion rings were beneficial.

But I also give credit to a number or less-noticed supplements, e.g. boron. It's compicated.

Best, -Patrick

[PhilipSZacarias in reply to pjoshea13]

I agree, but there are no good sources of apigenin and fisetin in adequate dosage forms and verified quality (unless you have a line on them). I am taking boron, mainly for maintenance of bone strength and for its (little reported) anti-PCa properties. Cheers, Phil

[pjoshea13 in reply to PhilipSZacarias]

Phil,

I recently switched to:

store.revgenetics.com/produ...

for Fisetin. I use their micronized resveratrol.

-Patrick

[Shanti1 in reply to pjoshea13]

Thanks Patrick, I was looking for a high dose source.

[PhilipSZacarias in reply to pjoshea13]

Many thanks...I will peruse!

[Hidden in reply to pjoshea13]

Thanks for the fisetin info. I came across this site fightaging.org/archives/201... that includes a mention in the comments section about the negative effect of fisetin on telomeres via shortening them (related paper mcr.aacrjournals.org/conten... ). Can you comment on that? Thanks!

[pjoshea13 in reply to Hidden]

The people who want to live forever focus on telomere length & the possibility of reviving telomerase. For those in the cancer years, this should be a scary idea, i.e. the idea of making cells immortal. But, of course, cancer cells eventually learn to get around the Hayflick Limit anyway.

The idea that a cancer treatment might prematurely shorten telomere length is a concern. I think that it is optimistic for anyone with advanced PCa to be thinking really long term. We make certain trade-offs. ADT has cardio-downsides, for instance.

I hope that fisetin doesn't age me much faster than normal.

A good way to age slower is to adopt a selective amino acid restriction diet. It will slow the rate of cell division & help preserve those telomeres.

So much to worry about these days. LOL

Best, -Patrick

[GeorgeGlass in reply to pjoshea13]

But wouldn’t you agree that some amino acids are beneficial for us, such as: taurine, arginine and citrulline?

[CalBear74 in reply to pjoshea13]

Patrick, are you aware of any research indicating that the above as supplements would interfere with blood pressure medications? I am particularly concerned about turmeric/curcumin.

Thank you for your contribution at this site. It is marvelous!

[pjoshea13 in reply to CalBear74]

Thanks!

Seems that curcumin is anti-hypertensive:

ncbi.nlm.nih.gov/pmc/articl...

This is a meta-analysis:

pubmed.ncbi.nlm.nih.gov/316...

Full text:

sci-hub.tw/10.1016/j.phrs.2...

Best, -Patrick

P.S. It's a good general question. See:

pubmed.ncbi.nlm.nih.gov/229...

"The effect of polyphenol consumption on blood pressure"

[CalBear74 in reply to pjoshea13]

Thanks again Patrick. I will maintain my curcumin supplementation.

[cesces]

Wow, Nice.

[Captain_Dave]

My favorite supplement quercetin can be added to the list also:

Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells

pubmed.ncbi.nlm.nih.gov/112....

And if you are concerned about Covid here is some quercetin info:

Quercetin and viral infections

Preclinical data indicate that quercetin exhibits antiviral properties. One mechanism by which quercetin exerts its beneficial effects might lie in its capacity to serve as an ionophore. An ionophore is a compound that can transport ions across the semipermeable lipid bilayer that surrounds cells. Of particular relevance in viral disease is the movement of zinc, an essential nutrient that inhibits the action of RNA-dependent RNA polymerase — the enzyme critical for the reproduction of RNA viruses such as SARS-CoV-2, the virus responsible for COVID-19.[27] Essentially, zinc blocks the replication of viruses. However, zinc is a positively charged ion and cannot enter cells to perform this function without a transporter. Quercetin is a known ionophore. Although the compound has not been clinically tested against SARS-CoV-2, clinical trials are beginning, with outcomes expected in a few months.

foundmyfitness.com/topics/q...

-Capt. Dave

[LearnAll in reply to Captain_Dave]

Not just virus infected cell..but any deformed cell such as cancer cell gets killed if Zinc is able to enter inside in sufficient quantity. For that Zinc ionophore is needed which pushes Zinc inside the these deformed, irregular cancer cells. Zinc ionophores include Clioquinol, Hydroxy-chloroquin and of course your favorite ..Quercetin. My bitter liquid includes 10 drops of Ionic Zinc in 10 ml of red onion juice and the cancer killer weapon is ready to go.

[PhilipSZacarias in reply to LearnAll]

Disulfiram (antabuse) is also a zinc (copper) ionophore. Cheers, Phil

[GeorgeGlass in reply to LearnAll]

I have been told for years that zinc supplements promote prostate cancer growth. Is that not true?

[LearnAll]

pubmed.ncbi.nlm.nih.gov/325...

Very very large sample size epidemiological study about polyunsaturated fatty acids and cancer...also very recent year 2020.

[Wings-of-Eagles]

Sounds like deleted