Metformin and Valproic Acid

[pjoshea13]

New study below [1].

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 [2].

"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"> [3].

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."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/288...

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.

Author information

1

Department of Urology, University of medicine and pharmacy at Ho Chi Minh city.

2

Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre.

3

South Australian Health and Medical Research Institute, University of Adelaide, School of Medicine and Freemasons Foundation Centre for Men's Health.

4

Molecular Medicine and Pathology, Flinders University and Medical Centre.

5

Flinders Centre for Innovation in Cancer, Flinders University and Medical Centre [e-mail].

Abstract

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

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

[3] ncbi.nlm.nih.gov/pubmed/?te...

[BigRich]

Parick,

I hope you have a medical doctor that thinks outside the box.

Rich

[Neal-Snyder in reply to BigRich]

So do I. And I hope I have one. I sent what you wrote to my PCP, Patrick, & made my request. Thank you very much for providing the information, Patrick.

Neal

[Kuanyin]

Unlike Metformin, Valproic Acid does not present such a benign usage profile. What follows is only one of many toxicity warnings regarding this medication.

Neurotoxic Effects of Pharmaceutical Agents III: Neurological Agents

Kara A. Kennedy, Melody Ryan, in Clinical Neurotoxicology, 2009

Valproic Acid

Valproic acid is available in the form of valproate sodium and divalproex sodium, both of which are rapidly converted to valproic acid once administered. Valproic acid's mechanism of action appears to be related to an indirect increase in regional brain GABA levels, an inhibitory neurotransmitter.49 It also inhibits T-type calcium channels.50

When valproic acid serum concentrations are within therapeutic range, CNS effects, such as somnolence and dizziness, occur in up to 25% of patients but are most often mild in severity and resolve with dose reduction.51 Movement disorders, such as tremor or parkinsonism, can occur with valproic acid use. Chronic treatment with valproic acid causes symptomatic tremor in about 10% of patients.52 The tremor may be alleviated by dosage decrease, discontinuation of the medication, or use of a symptomatic agent, such as propranolol or amantadine.52 Parkinsonism is reported to occur in approximately 5% of patients on valproic acid.53,54 The odds of having parkinsonism are five times higher with valproic acid than with other antiepileptic drugs.53 The symptoms are quickly resolved by discontinuation of the medication.53

[pjoshea13]

And yet:

"Valproate is included in the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system." (Wiki)

"safe"

If one looks up the side effects of Avodart, say, one might to decline to use it.

& Xtandi is no walk in the park.

It comes down to context. Nalakrats & I aren't using VA, but we have it in mind.

-Patrick

[Kuanyin]

Can't compare with Avodart: fortunately, or unfortunately, it's an important element of our androgen blockade treatment: we really don't have much choice here. None of the approved drugs we take doesn't require a "pound of flesh" in return for their use. However, Valproic Acid is much more "elective." There are many other things we can do or take that present a less toxic profile. Our bodies (liver, kidneys, etc.) can only take so much insult before they rebel. I guess, what it gets down to in the case of Valproic Acid is this, is the game worth the candle? For me, at least for now, the answer is no.