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.
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?
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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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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so what does this mean for us?
http://www.ehrs.org/conferenceabstracts/2000marburg/guestlectures/s04-sawaya.htm
The abstract brainbug posted from the EHRS conference mentions AR protein being highly over-expressed in the scalp of patients 6 months after stopping treatment with finasteride.
The studies show an association between the Pura(Pur-Alpha) protein and AR over-expression and show that AR over-expression can be reduced by increasing Pura levels via epigenetic modulators(acting on the Pura encoding gene itself?) or by introducing Pura-producing DNA into the androgen independent cells.
So, if a key component of PFS is persistent overexpression of androgen receptors, then increasing intracellular Pura levels by whatever means could possibly be a treatment option for PFS.
can you tie the over-expressed androgen receptor problem with the Italian studies findings of altereed neuroactive steroids?
Most certainly. The etiology of an overexpressed AR signal ties in perfectly with the findings of depleted neurosteroids.
So what came first the chicken or the egg? In other words has depleted neurosteroid levels lead to potential poor gene expression or an overexpressed androgen receptor?
Overexpressed AR led to depleted neurosteroid levels due to lack of induction of enzymes.
Any possibility that progesterone down regulates AR? Looks like another person is improving via lightattheend’s protocol.
How?
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my balls become smaller now.
and in 2 years i have pfs , my balss never got smaller, it was always big.
so i don’t know what the broccoprotect did to me.
very interesting and plausible theory. I will do more research on this. Panobinostat is fairly easy to get ahold of…
how could i increase the AR?
Just wondering if anyone else tried NYScientist’s protocol and had any joy with it, or is interested in it? Jonson, hope you have recovered from the adverse effects it gave you.
Hey guys,
It’s been a while and thought I owed an update. I haven’t checked the site for a while simply because I just have been feeling better to a level where I am more than satisfied and to be honest, I just forgot. Since my last long post where I went through all the changes, I have actually gotten slightly better. I would say about 60-70% of where I was pre-fin (up from 25-30% at my lowest). Erections are maybe even 80%-85% of where they were pre-fin. As mentioned before the sexual desire improved but not to the same level as physical–regardless I am very satisfied with where I am.
To answer someone’s question, the way I did it was to take one single dose of 8-12 pills at a time and then wait it out for a month to see if I noticed any effects. Then a couple months later I tried again (i went from 8 to 10 to 12 pills at a time, for a total of 3x). I didn’t feel anything right away, however I noticed that gradually over the course of the months I started to improve. The funny thing is that it has been a year since the last dose I took and I have still seen gradual improvement. One thing that may have helped is that I started to get in shape, doing a lot more cardiovascular activities and moderately heavy lifting (on a side note, squats/leg presses I noticed had a clear positive impact on libido). At this point, I am comfortable saying that I have definitely seen a real and significant measurable improvement. This is not just an “I think I feel a bit better”. I am absolutely sure I have improved.
I can never be sure that it was the BroccoProtect, but it definitely marked the start of my gradual improvement. At minimum, the takeaway is that it is very possible to recover close to fully over time. Heck, it may have just been nothing else but time passing and my body reverting back to its normal state so hopefully it brings some optimism to you guys that things can get better on their own. I am going to take another dose in the near future and will let you guys know if I see continued gains.
Cheers
I just posted this under another topic. However seeing as this a topic in regards to epigenetic modulation I thought I’d post just one of the pieces of research I have found:
D’Addario, C., Di Francesco, A., Pucci, M., Finazzi Agrò, A., & Maccarrone, M. (2013). Epigenetic mechanisms and endocannabinoid signalling. FEBS Journal,280(9), 1905-1917.
• It has also been observed that THC and cannabinol can (a) activate the ERK-MAPK cascade, a crucial event for gene activation during mitosis induction, and (b) inhibit gap-junction intercellular communication, required to relieve growth suppression of cells [107].[/u]
• Altogether, these results show a new activity of eCB’s as transcriptional repressors via epigenetic mechanisms and in, in the search of drugs able to reverse methylation abnormalities, they suggest a possible exploitation of eCB signaling in human diseases where DNA methylation is downregulated.
• eCB-mediated transcription involves coordinated interactions of CB receptors with acetylases and deacetylases, methylases and demethylases. In addition, eCBs have the potential to trigger extranuclear signaling that activates several kinase cascades, which either directly modify histone tails or indirectly influence functions and/or recruitment of histone-modifying enzymes.
• Indeed, epigenetic alterations are reversible and specific interventions that target different epigenetic pathways might have a major impact on health problems, eventually providing a new avenue for innovative therapeutic approaches.
Seeing as I’ve only posted a small part, I’ll point out that stimulation of the endocannabinoid system was done with THC and CBD. 2 cannabinoids found in cannabis.
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How did you pace out the 8, 10 and 12? If you were doing it all again how would you go about it?
May give this a try. Why not…
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There is truth to the lower body workout, I feel more horny and better after a lower body workout. Before, during and after the crash I have been on HRT as well as working out consistently with weight training, I am sure that has helped me to not be as bad as otherwise I would be. My HRT doctor seems to insist that I will recover in time, so I am starting to think that the only thing we can do is let our body’s recover, but these kinds of things may boost it a bit.