Hey Guys,
I posted this over on my other thread but thought I’d post it here as well for consideration:
Hey guys, this is another interesting article I found on valproic acid (HDAC inhibitor) enhancing androgen responsiveness (albeit in vitro).
Histone deacetylase inhibitor valproic acid suppresses the growth and increases the androgen responsiveness of prostate cancer cells.
ncbi.nlm.nih.gov/pubmed/21862211
Valproic acid, also known as Depakote is an HDAC inhibitor used for bipolar disorder. Normally it is associated with a decrease in libido when used constantly, however the exciting thing that this paper found, is that if you pre-treat an androgen resistant prostate cell line for 2 days, and then treat with androgen (DHT), it increased androgen responsiveness (as measured by growth) by 70-120%! Now this is a study done in cells, but since Depakote is an approved prescription drug, it should be really easy for someone to try this out. Does anyone have means of (legally) obtaining some Depakote?
I’ve included the specific paragraph of interest below:
"…We thus investigated the effect of HDAC inhibitor on androgen-responsive cell growth. Androgen-independent C-81 cells were treated with 1 mM VPA for 48 h followed by 10 nM DHT in a steroid-reduced condition. The usage of 10 nM DHT is to determine if VPA pre-treatment can increase the common androgen-responsiveness of cell growth. In the presence of DHT for 48 h, the growth of VPA-pretreated C-81 cells increased by about 70% (column #4 vs. #3, Fig. 3B, left panel, p < 0.01), compared with only about 35% increase of control cells without VPA pre-treatment (column #2 vs. #1, Fig. 3B, left panel). Western blot results validated that the cPAcP 50 kDa mature form protein was elevated by VPA treatment (lane #3 vs. #1, Fig. 3B, right panel), which was decreased by subsequent DHT-treatment (lane #4 vs. #3, Fig. 3B, right panel), inversely correlating with cell growth stimulation [20], [27] and [28]. In parallel, cellular PSA level was greatly elevated by DHT in VPA-pretreated cells, about 1.5-fold of that in control cells without VPA-pretreatment (lane #4 vs. #2, Fig. 3B, right panel). In those same cells, AR expression level was not significantly changed after a total of 5 days treatments including 2-day by VPA and 3-day by DHT.
Due to the clinical importance of androgen sensitivity of PCa cells, we investigated whether VPA treatment could similarly increase the degree of androgen responsiveness in other androgen-independent PCa cells, including LNCaP C4-2 and MDA PCa2b-AI cells. As shown in Fig. 3C for LNCaP C4-2 cells and Fig. 3D for MDA PCa2b-AI cells, DHT alone could increase the basal cell growth by approximately 10% (column #1 vs. #2). Interestingly, DHT could greatly increase the growth of VPA-pretreated cells by about 70% and 120%, respectively, (column #4 vs. #3, Fig. 3C and D, left panels). We subsequently validated DHT effect by semi-quantifying PSA levels in those treated cells. Interestingly, PSA basal level was elevated in VPA alone-treated MDA PCa2b-AI cells in the absence of DHT (lane #3 vs. lane #1, Fig. 3D, right panel). Importantly, cellular PSA level was greatly elevated by DHT in VPA-pretreated cells, approximately 4- and 9-fold of that in control cells without VPA-pretreatment, respectively (lane #4 vs. #2, Fig. 3C and D, right panels). It should also be noted that due to the low expression level of AR protein in these two PCa cell lines, comparing with LNCaP C-81 cells, a prolonged hybridization with primary Ab to AR with longer exposure time periods was required. In summary, VPA pre-treatment enhances DHT effect on the increments of cell growth and PSA expression, which indicates that HDAC inhibitors can enhance androgen responsiveness of PCa cells."
After writing this, I did a search and saw that Awor mentioned trying Valproic Acid at one point. I will reach out to him and see if he ever used it.
One important point that this article brings up is that HDAC like Valproic Acid may suppress androgen activity when on them, but have androgen response enhancing properties when getting off. Thus when testing these agents, in some cases the most effective way may be to pre-treat with the HDAC inhibitor, then treat with testosterone gel after to determine if response to androgen goes up
