Re-Expression of ... AR in Receptor Negative Endocrine Cancers via GSK3 Inhibition. Lithium?

[pjoshea13]

New study below [1]

Might interest those who have treatment-emergent loss of androgen receptor [AR].

"GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, and bipolar disorder." [2]

"It has now been shown that lithium, which is used as a treatment for bipolar disorder, acts as a mood stabilizer by selectively inhibiting GSK-3." [2]

"In diabetes, GSK-3β inhibitors increase insulin sensitivity, glycogen synthesis, and glucose metabolism in skeletal muscles, and reduce obesity by affecting the adipogenesis process. GSK-3β is also over expressed in several types of cancers, like colorectal, ovarian, and prostate cancer." [2]

"Treatment with a novel and more selective inhibitor of GSK3 resulted in decreased methylation of the promoter region of genes encoding the Androgen Receptor (AR) ... and re-expression of the AR ,,, in AR negative prostate cancer ... cells ..." [1]

If AR can be restored, the cells will again become responsive to drugs that target the AR-axis.

Lithium?

A 2016 study that used lithium chloride [LiCl] on stem-like PCa cells, reported a biphasic effect:

"To the best of our knowledge, the present study showed for the first time that the effects of LiCl on PCa stem cells are also concentration-dependent/biphasic, as in normal prostate cells ..." [3]

Life Extension recently suggested that low-dose lithium (orotate?) might ward off Alzheimer's, but it appears that low-dose might not be appropriate in those with PCa.

Of interest [4] - "Lithium Carbonate was administered to eight patients for four weeks prior to radical prostatectomy ..."

Anyone here using lithium? What kind & what dose?

Looks like one should discuss with one's doctor before experimenting.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/354...

[2] en.wikipedia.org/wiki/GSK-3...

[3] ncbi.nlm.nih.gov/pmc/articl...

[4] urotoday.com/conference-hig...

[beckymb3]

Wish I could understand the info you posted better! Very detailed! Here is another related article. frontiersin.org/articles/10...

[pjoshea13 in reply to beckymb3]

Hi Becky,

Nice find! A much easier read - for the most part.

Interesting suggestion at the end of the Discussion section:

"One possible piece of low-hanging fruit for a clinical trial would be low- to medium-dose lithium for men undergoing active surveillance (AS) for advance of prostate cancer. From studies of AS outcomes, a large fraction of patients on AS ultimately require invasive treatment, as reviewed by Dall'Era et al. (71). When this need arises it typically comes after only a few years. Thus, a trial of lithium in this context would produce significant results in a short time and would be relatively inexpensive.

"A second area that seems ready for clinical trial is augmentation of other cancer therapies, either radiation or pharmaceutical, with low-to-moderate lithium. Studies we have cited in this paper support the possibility of beneficial results, and also support the lack of side effects from such lithium doses."

Thanks, -Patrick

[beckymb3 in reply to pjoshea13]

In your post yesterday you said low dose might not be appropriate for PCa. But I didn't "get" the article well enough to understand your thinking. I'm familiar with Bipolar lithium and with OTC lithium orotate. Why would orotate not be helpful for PCa? Or would it? Thanks, Becky

[pjoshea13 in reply to beckymb3]

I'm wondering why there hasn't been interest in lithium?

It seems as though the orotate might be useful, but at what dose? If lithium has a biphasic effect on PCa, we need to know the minimum dose to avoid growth stimulation. (As well as the maximum safe dose - to avoid side effects.)

-Patrick

[noahware]

" it appears that low-dose might not be appropriate in those with PCa "

Does this mean it may simply offer no benefit, or that it may do actual harm?

I read years ago that regions with higher levels of lithium in well water appeared to have lower rates of depression and suicide. Some other potential benefits of low-dose lithium were noted, and no apparent harms, so I figured, why not?

I took 1 or 2 a day of 5mg of lithium orotate for a time, but that was years ago. If there was a benefit, it was not one I could perceive. (My mood swings remained, and my personal suicide rate remained at zero, with suicidal thoughts popping up at about the same rate I've always experienced since a teen).

Readers should note: the doses used for bipolar are massive!

[pjoshea13 in reply to noahware]

"Biphasic" - having the opposite effect at low levels. This has been observed for genistein too.

(and I believe it true of testosterone when estradiol is high. i.e. growth-permissive when E2:T is high, but protective when E2:T is low. Pre-ADT, that is.)

-Patrick

[noahware in reply to pjoshea13]

That parenthetical comment seems (to me) to sum up my very rapid progression when my tE2 attempt at ADT failed: the high levels of E2 I got from the patches did not get me castrate, but only dropped my normally high T levels to 100-150... recipe for disaster!