Non-PCa Prescription Drugs: Valproic ... - Advanced Prostate...

Advanced Prostate Cancer

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Non-PCa Prescription Drugs: Valproic Acid / Valproate

8 years ago•6 Replies

This is the first of a new series of posts prompted by a new Valproic Acid [VPA] study [14]. A recent population study [13] is worth noting too.

It must be 6 years since my doctor turned down my request for Valproic Acid. He had just turned down my request for Metformin & I was pulling his leg by asking. But I was intrigued by what I had read & wanted his reaction.

VPA is an established drug (over fifty years). "In the United States it costs about 0.90 USD per day."

"Valproate (VPA), and its valproic acid, sodium valproate, and divalproex sodium forms, are medications primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches. It is useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. It can be given intravenously or by mouth. Long acting formulations exist." [1]

Many changes that happen in PCa cells are not due to mutation, but to epigenetic changes caused by hypermethylation or histone deacetylase [HDAC]. VPA is a HDAC inhibitor. As such, it restores the activity of genes silenced by HDAC.

DNA is stored as a tight ball, where segments are wrapped around proteins (histones). When genetic information needs to be read, so that anti-PCa proteins can be transcribed, histone acetylase causes a loosening of the strand from its histone. PCa silences genes by creating histone deacetylase, to prevent the unraveling. VPA is known to inhibit that.

[2] This was first reported in 2004 (Germany), & there has been little research funding in America, for obvious reasons (it is a cheap generic drug):

"Valproic acid treatment caused a marked inhibition of histone deacetylases activity. Expression of prostate-derived Ets transcription factor and consequently prostate-specific antigen were down-regulated to basal levels in LNCaP cells. Pro-apoptotic factor caspase-3, tissue inhibitor of matrix metalloproteinase-3 and insulin-like growth factor binding protein-3 were up-regulated resulting in apoptosis of tumor cells."

"Our study provides strong evidence that prostate cancer may benefit particularly from anti-proliferative stimuli from this well established drug."

[3] (2006 study - China) reported a "profound decreases in proliferation, independently of androgen regulation." "Moreover, chronic VPA treatment results in statistically significant reduction of tumor xenograft growth in vivo."

[4] (2006 - Italy): "We observed that valproic acid was a potent and early apoptotic inducer, mainly in less-differentiated prostate cancer cell lines." "Our data indicate that the use of valproic acid may be a suitable therapeutic agent in the control of prostate cancer progression and its action appears particularly relevant in the control of refractory stages of prostate cancer."

[5] (2007 - U.S. - Johns Hopkins) "VPA may be functioning as an HDACI to inhibit growth of PCa cells in vitro and in vivo by modulating multiple pathways including cell cycle arrest, apoptosis, angiogenesis, and senescence."

[6] (2007 - China) "We conclude that chronic VPA results in profound decreases in the proliferation of PC3 cells, not only by increasing histone H3 acetylation and up-regulating p21CIP1/WAF1 expression, but also by down-regulating VEGF." (i.e. angiogenesis)

[7] (2007 - Germany) To my mind, a key turning point in PCa occurs when the estrogen receptor [ER] balance changes. ERbeta opposes pro-growth ERalpha. When ERbeta becomes down-regulated & ERalpha becomes up-regulated, an important protection is lost. "... we show that one prominent result of treatment with VPA or tectorigenin is the up-regulation of ERbeta resulting in antiproliferative effects."

[8] (2009 - Italy) The sad loss of PTEN in PCa cells is usually reported as a mutation, but: "Although the tumor-suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is frequently mutated or deleted in a wide variety of solid tumors, some malignancies, including prostate cancer, exhibit undetectable PTEN protein without loss of PTEN gene. Aim of this study was to evaluate whether the PTEN downmodulation, observed during bicalutamide {Casodex} treatment, was due to epigentic events."

"... 54 and 68% of primary cultures displayed detectable amounts of PTEN protein and mRNA, respectively." "Treatment with valproic acid was able to increase the percentage of PTEN-positive cultures up to 80 and 74% for PTEN protein and mRNA determination, respectively."

".. our data suggests that antiandrogenic therapy reduced PTEN expression by epigenetic mechanisms suggesting that epigenetic drugs, upmodulating PTEN expression, can reduce Akt activity and probably enhance the efficacy of antiandrogenic therapy."

{Worth noting if one is on Casodex.}

[9] (2011 - China)

"These results thus suggest that up-regulation of E-cadherin and inhibition of cell migration may represent a new anticancer mechanism of VPA."

[10] (2012 - U.S. - Johns Hopkins)

"VPA inhibits tumor growth by multiple mechanisms including cell cycle arrest, induction of differentiation, and inhibition of growth of tumor vasculature."

[11] (2013 - Germany)

"The re-expression of cyclin D2 observed in PCa cells is activated by increased histone acetylation in the promoter region of the Ccnd2 gene and represents one underlying molecular mechanism of VPA treatment that inhibits the proliferation of cancer cells. Altogether, our results confirm that VPA is an anticancer therapeutic drug for the treatment of tumors with epigenetically repressed cyclin D2 expression."

[12] (2015 - S.Korea)

"In the present study, we demonstrate that inhibition of cell viability and invasion by VPA was more effective in the metastatic prostate cancer cell line PC3 than in the tumorigenic but non-metastatic prostate cell line, RWPE2. Further, we identified that the metastasis suppressor NDRG1 is upregulated in PC3 by VPA treatment."

[13] (2016 - Finland)

"The study included all new prostate cancer cases diagnosed in Finland in 1995-2002 and matched controls (24,657 case-control pairs) identified from the Finnish Cancer Registry and the Population Register Center, respectively. Information on antiepileptic drug purchases was obtained from the national prescription reimbursement database."

"Compared to never-users of antiepileptic drugs, the overall prostate cancer risk was decreased among users of phenobarbital, carbamazepine, and valproic acid (multivariable-adjusted odds ratio (OR) 0.47 ... OR 0.82 ... and OR 0.62 .., respectively), but not among users of other antiepileptic drugs."

"Overall prostate cancer risk decreased in a dose-dependent manner by cumulative amount, duration and yearly dosage (intensity) of HDAC inhibitors valproic acid and carbamazepine."

"The risk of advanced prostate cancer was decreased only among carbamazepine users (OR 0.65 ...)"

[14] (2016 - China)

"These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway."

[W] VPA versus trichostatin-A. See: [Wa] [Wb] [Wc] [Wd]

[X] Some studies have used VPA as a baseline for drug comparison purpose, e.g. [Xa]

[Y] VPA plus another drug. See: [Ya] [Yb] [Yc] [Yd] [Ye] [Yf] [Yg] [Yh] [Yi] [Yj] [Yk] [Yl]

[Z] VPA & radiosensitizing. See: [Za] [Zb]

...

In my view, PCa future therapies will include one or two drugs that will reverse epigenetic changes. It is almost too good to be true that many changes in PCa cells are not permanent. By reversing those changes, we set the clock back to a point where PCa cells are more vulnerable.

Will VPA be part of the protocol? As time passes, it is more likely that a superior HDAC inhibitor will emerge. On the other hand, the drug is cheap & has a safety track record (in spite of acknowledged possible side effects).

Will VPA do all of the things reported in cell studies? My expectation is only that VPA will help other drugs do better what they were designed for.

-Patrick

[1] en.wikipedia.org/wiki/Valpr...

[2] ncbi.nlm.nih.gov/pubmed/146...

[3] ncbi.nlm.nih.gov/pubmed/168...

[4] ncbi.nlm.nih.gov/pubmed/170...

[5] ncbi.nlm.nih.gov/pubmed/174...

[6] ncbi.nlm.nih.gov/pubmed/177...

[7] ncbi.nlm.nih.gov/pubmed/179...

[8] ncbi.nlm.nih.gov/pubmed/197...

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

[10] ncbi.nlm.nih.gov/pubmed/230...