New study below .
A sense of deja vu here, since 6-7 years ago I asked my GP for both drugs. He declined.
I was able to get Metformin elsewhere, but not Valproic Acid.
Valproic Acid is described as an anti-epileptic drug, which it is .
"It also has histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid."
Many changes found in PCa cells are epigenetic (occuring 'above' the gene level.) As such, they can be reversed, since affected genes have not changed. One method of epigenetic silencing targets acetylation. Cellular DNA, which could otherwise wrap around the block, is tightly wrapped around proteins known as histones. In order for a region of DNA to be accessed, it has to be unravelled. The enzyme acetylase does that.
In PCa, key anti-cancer DNA regions are kept tightly bound via histone deacetylase [HDAC]. Valproic Acid is an HDAC inhibitor. As such, it can allow silenced genes to be activated.
There are now 65 PubMed hits for <prostate "Valproic Acid"> .
See my post of a year back: "Non-PCa Prescription Drugs: Valproic Acid / Valproate"
From the new paper:
"... we demonstrate that MET+VPA can synergistically kill more prostate cancer cells than either drug alone."
Mol Cancer Ther. 2017 Aug 11. pii: molcanther.0074.2017. doi: 10.1158/1535-7163.MCT-17-0074. [Epub ahead of print]
The combination of metformin and valproic acid induces synergistic apoptosis in the presence of p53 and androgen signaling in prostate cancer.
Tran LNK1, Kichenadasse G2, Butler LM3, Centenera MM3, Morel KL2, Ormsby RJ2, Michael MZ2, Lower KM4, Sykes PJ5.
Department of Urology, University of medicine and pharmacy at Ho Chi Minh city.
Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre.
South Australian Health and Medical Research Institute, University of Adelaide, School of Medicine and Freemasons Foundation Centre for Men's Health.
Molecular Medicine and Pathology, Flinders University and Medical Centre.
Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre firstname.lastname@example.org.
We investigated the potential of combining the hypoglycemic drug metformin (MET) and the anti-epileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced anti-tumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET+VPA was assessed in cell lines using RNA interference in LNCaP (p53+) and ectopic expression of p53 in PC-3 (p53-). The role of the androgen receptor (AR) was investigated using the AR antagonist, Enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET+VPA. Knock-down of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53-, AR-) increased apoptosis in response to MET+VPA. In patient-derived prostate tumor explants, MET+VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET+VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo pre-clinical studies are required to determine the relative efficacy of MET+VPA as a potential treatment for prostate cancer.
Copyright ©2017, American Association for Cancer Research.
PMID: 28802253 DOI: 10.1158/1535-7163.MCT-17-0074