Restoring androgen sensitivity with epigenetic modulators

#41

He said 10 at one time (at once or over the course of a few hours) and he weighs 185. You might have to adjust for your weight. He saw results after a few weeks.

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#42

Do you think that it is worth trying?

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#43

What I’m confused about is that he wrote:

So it sounds like he took 8 pills, all at once, and then nothing more for several weeks. Then he took 10 pills, all at once, and a few weeks later felt results. No pills in between – just a total of 18. As opposed to what he’d been doing before, which involved taking 8/day every day. A very big difference. Just trying to be clear on exactly what he did. This seems like a very hopeful thread.

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#44

You missed his entire point. Go back and read his posts more carefully.

He stated – “During this time I reviewed the papers I referenced at the start of this thread, and realized that they typically just did a short treatment upfront, and this was sufficient to confer a persisting effect of resensitization to hormone. I thought that maybe it wasn’t as important to maintain steady state levels of sulforaphane, but rather to reach a concentration high enough for the compound to reach therapeutic levels and cause an acetylation event to occur.”

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#45

Yeah, I get that, I think. I wanted to make sure I was understanding it right – that what achieved results was basically two separate mega-doses, spaced a few weeks apart. Seemed a little unclear to me, hence I figured I’d ask.

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#46

so i ordered this broccoprotect , i will try it soon.

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#47

Just thought I shared an interesting article. Talks about needing to use a combination of drugs in order to reactivate anticancer genes. Maybe we need combination as well. Thats why its important to support the research.

sciencedaily.com/releases/20 … 094925.htm

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#48

like what drugs?

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#49

Thats what the research is for… figuring out what drug or combination of drugs could be used to reverse any epigenetic changes.

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#50

““We showed in the late 1990s that if you got rid of the abnormal DNA methylation first, and then used a histone deacetylase inhibitor, you could enhance the re-expression of these abnormally silenced genes,” Baylin says…In addition to showing that the combination epigenetic therapy is well-tolerated and can be effective, the study, Rudin says, suggests that the silencing status of these four key genes may represent a “biomarker” of benefit from the combination therapy in non-small-cell lung cancer. It also suggests, he says, that the combination of azacitidine and entinostat can show favorable epigenetic effects at much milder doses than the cell-killing doses at which azacitidine was originally used in cancer patients.”

(sciencedaily.com/releases/20 … 094925.htm)

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#51

any news about that?

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#52

i took yesterday 1 capsule of broccoprotect, i will take 8-10 today.

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#53

I took 8 capsula of broccoprotect 5 days ago.
I think i feel worse, same feeling when i tried zinc.

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#54

I tried this experiment about three weeks ago and I will be trying it again. Although I felt worse at first, I saw the following benefits:

Increased sweat on hands and feet, skin feels smoother
Skin on back feels smoother
receding hair line
genitals smell more
penis less rubbery
fewer muscle twitches

Unfortunately, these benefits are starting to go away. I’m thinking it may be due to the fact I’ve been masturbating more and orgasm increases prolactin, which increases androgen receptor, which would undo the benefits of sulforaphane.

Also, the muscle twitches was interesting and I did some searching and came up with an article that says sulforaphane epigenetically represses myostatin. When you repress myostatin, your muscles can repair more. Body builders use it to help build muscle. I didn’t have muscle wastage (at least not noticeably), but I did notice a lessening of my muscle twitches with sulforaphane. I want to try adding tyrosine to increase dopamine to control prolactin.

Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells.

Fan H, Zhang R, Tesfaye D, Tholen E, Looft C, Hölker M, Schellander K, Cinar MU.
Source
Institute of Animal Science, Animal Breeding and Husbandry Group, University of Bonn, Bonn, Germany.
Abstract
Satellite cells function as skeletal muscle stem cells to support postnatal muscle growth and regeneration following injury or disease. There is great promise for the improvement of muscle performance in livestock and for the therapy of muscle pathologies in humans by the targeting of myostatin (MSTN) in this cell population. Human diet contains many histone deacetylase (HDAC) inhibitors, such as the bioactive component sulforaphane (SFN), whose epigenetic effects on MSTN gene in satellite cells are unknown. Therefore, we aimed to investigate the epigenetic influences of SFN on the MSTN gene in satellite cells. The present work provides the first evidence, which is distinct from the effects of trichostatin A (TSA), that SFN supplementation in vitro not only acts as a HDAC inhibitor but also as a DNA methyltransferase (DNMT) inhibitor in porcine satellite cells. Compared with TSA and 5-aza-2’-deoxycytidine (5-aza-dC), SFN treatment significantly represses MSTN expression, accompanied by strongly attenuated expression of negative feedback inhibitors of the MSTN signaling pathway. miRNAs targeting MSTN are not implicated in posttranscriptional regulation of MSTN. Nevertheless, a weakly enriched myoblast determination (MyoD) protein associated with diminished histone acetylation in the MyoD binding site located in the MSTN promoter region may contribute to the transcriptional repression of MSTN by SFN. These findings reveal a new mode of epigenetic repression of MSTN by the bioactive compound SFN. This novel pharmacological, biological activity of SFN in satellite cells may thus allow for the development of novel approaches to weaken the MSTN signaling pathway, both for therapies of human skeletal muscle disorders and for livestock production improvement.

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#55

I took 8 capsules a week ago, i still feel worse and it is harder to get an erection.
I will see if it is change.

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#56

I also tried this without any noticeable benefit. I do think the reasoning behind trying it is very sound but maybe for some of us more severely effected it might take some combination therapy to address methylation first as another poster had mentioned.

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#57

Ok i am still feel worse and it became scary like i am back to the worst days when i stopped propecia.
What can i do to reverse it?

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#58

HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.
Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP.
Source
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
Abstract
The molecular chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the activity and stability of these signaling proteins, Hsp90 has emerged as a critical modulator in cell signaling. Here, we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from an essential cochaperone, p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Our results identify Hsp90 as a target of HDAC6 and suggest reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity.

I think Awor posted this article before. Apparently androgen hypersensitivity is mediated by HSP90 which is mediated by HDAC6. So I guess we should be trying HDACis that target HDAC6?

pubs.acs.org/doi/abs/10.1021/jm301355j

en.wikipedia.org/wiki/Hydroxamic_acid

“Some hydroxamic acids (e.g. vorinostat, belinostat, panobinostat, and trichostatin A) are HDAC inhibitors with anti-cancer properties.”

Has anyone tried any of these?

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#59
  1. hmg.oxfordjournals.org/content/1 … 5.abstract

Androgen Receptor Overexpression in Prostate Cancer Linked to Purα Loss from a Novel Repressor Complex
Longgui G. Wang1, Edward M. Johnson2, Yayoi Kinoshita3, James S. Babb1, Michael T. Buckley1, Leonard F. Liebes1, Jonathan Melamed1, Xiao-Mei Liu1, Ralf Kurek4, Liliana Ossowski3, Anna C. Ferrari1
Author Affiliations
1.
1New York University Cancer Institute, New York, New York; 2Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia; 3Mount Sinai School of Medicine, New York, New York; and 4Stadtische Kliniken, Offenbach, Germany

Requests for reprints: Anna C. Ferrari, New York University Cancer Institute, New York University School of Medicine, 8th Floor, 160 East 34th Street, New York, NY 10016. Phone: 212-731-5389; Fax: 212-731-5455; E-mail: anna.ferrari@nyumc.org.
Abstract
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5′-untranslated region contains Purα and hnRNP-K. Purα expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Purα expression reduced AR at the transcription and protein levels. Purα knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Purα protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Purα is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Purα and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC. [Cancer Res 2008;68(8):2678–88]
cancerres.aacrjournals.org/conte … 2678.short
Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Purα-mediated decrease in androgen receptor levels
XiaoMei Liu1, Alejandro Gomez-Pinillos1, XiaoJun Liu1, Edward M. Johnson2, Anna C. Ferrari1,*
Article first published online: 29 SEP 2009 DOI: 10.1002/pros.21051
Abstract
BACKGROUND
Increased androgen receptor (AR) levels support resistance to apoptosis and hormone therapy in advanced prostate cancer (PC). We recently linked the overexpression of AR in androgen-independent LNCaP cells (AI-cells) and tissues from castration-resistant patients to decreased nuclear levels of Pur-alpha (Purα) and loss from a protein complex bound to repressor sequences (ARS) in the 5′-UTR of AR. Strategies to regain control of increased AR transcription may overcome resistance of AI-cells and improve treatment outcomes.
METHODS
MTT, real-time PCR, Western blot, ChIP, flow cytometry, and caspase 3/7 activation measured the effect on growth and targets of LBH589/bicalutamide treatment of AI-cells and androgen-dependent LNCaP cells (AD).
RESULTS
Within 16 hr of treatment of AI-cells with low concentrations of the histone deacetylase inhibitor LBH589, a shift of cytoplasmic Purα restored the nuclear levels and the binding of Purα to the ARS. This was followed by a decline in AR-mRNA and protein reaching levels of parental AD-cells. The fraction of AI-cells in G1 increased and the cells in S phase decreased similar to AD-cells, and there was a modest caspase activation. Most notably, treatment of bicalutamide-resistant AI-cells with 10 nM LBH589 combined with 12.5 μM bicalutamide synergistically inhibited cell growth and induced a fivefold higher level of caspase 3/7 activation than observed in AD-cells.
CONCLUSIONS
Low-dose LBH589 restores Purα binding to ARS and down-regulates AR transcription. Biologically, LBH589 reverses the resistance of AI-cells to bicalutamide and to apoptosis. The combination may restore the hormonal response of castration-resistant PC patients. Prostate 70: 179–189, 2010. ©2009 Wiley-Liss, Inc.
onlinelibrary.wiley.com/doi/10.1 … 1/abstract

“All scalp biopsies from patients obtained 6 months after finasteride treatment revealed intense upregulation of AR expression in comparison to pre-treatment biopsies of the same patient,”
ehrs.org/conferenceabstracts … sawaya.htm

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#60

so what does this mean for us?

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