Melatonin

[pjoshea13]

New study below. [1]

While there are a good number of PCa studies that report on the effects of disturbing the circadian rhythm, few look at the therapeutic use of melatonin.

The study confirms its anti-androgen effects - the androgen receptor was excluded from the nucleus of the cell. (Translocation of AR to the nucleus is necessary for its activities.)

"IGFBP3 and IGF1R were up- and downregulated, respectively"

IGF is the insulin-like growth factor, & there is extensive literature on the role of IGF-I in PCa profression.

IGFBP3 is the main IGF binding protein. It is down-regulated in PCa, which results in higher levels of free (bioavailable) IGF-I. Restoring IGFBP3 lowers available IGF-I.

IGF1R is the receptor for IGF-I, & it's good to see it downregulated.

(I doubt that many PCa professionals subscribe to the Journal of Pineal Research.)

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/277...

J Pineal Res. 2016 Oct 13. doi: 10.1111/jpi.12373. [Epub ahead of print]

IGFBP3 and MAPK/ERK signaling mediates melatonin-induced anti-tumor activity in prostate cancer.

Mayo JC1,2, Hevia D3, Quiros-Gonzalez I4, Rodriguez-Garcia A3, Gonzalez-Menendez P3,5, Cepas V3,5, Gonzalez-Pola I3,5, Sainz RM3,5.

Author information

1Departamento de Morfología y Biología Celular. University of Oviedo, Julián Clavería 6, 330006, Oviedo, Spain. [e-mail].

2Redox Biology Unit. The University Institute of Oncology of Asturias (IUOPA). University of Oviedo. [e-mail].

3Departamento de Morfología y Biología Celular. University of Oviedo, Julián Clavería 6, 330006, Oviedo, Spain.

4Department of Physics, Cambridge Research UK, University of Cambridge.

5Redox Biology Unit. The University Institute of Oncology of Asturias (IUOPA). University of Oviedo.

Abstract

Treatment of prostate cancer (PCa), a leading cause of cancer among males lacks successful strategies especially in advanced, hormone-refractory stages. Some clinical studies have shown an increase in neuroendocrine like cells parallel to the tumor progression but their exact role is a matter of debate. The prostate is a well-known target for melatonin, which reduces PCa cells proliferation and induces neuroendocrine differentiation. To evaluate the mechanisms underlying the indole effects on neuroendocrine differentiation and its impact on PCa progression, we used a cell culture model (LNCaP) and a murine model (TRAMP). Persistent ERK1/2 activation was found in both, melatonin and androgen-deprived cells. Melatonin blocked nuclear translocation of androgen receptor (AR), thus confirming anti-androgenic actions of the indole. However, by using a comparative genome microarray to check the differentially expressed genes in control, melatonin or androgen-deprived cells, some differences were found, suggesting a more complex role of the indole. By comparing control cells with those treated with melatonin or depleted of androgen, a cluster of 26 differentially expressed genes (± 2.5-fold) was found. Kallikreins (KLK)2 and KLK3 (PSA) were dramatically downregulated by both treatments whereas IGFBP3 and IGF1R were up- and downregulated, respectively, in both experimental groups, thus showing a role for IGF in both scenarios. Finally, melatonin prolonged the survival of TRAMP mice by 33% when given at the beginning or at advances stages of the tumor. Serum IGFBP3 was significantly elevated by the indole in early stages of the tumor, confirming in vivo the role of the IGF signaling in the oncostatic action of the indole. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

IGFBP3; TRAMP mice; androgen signaling; melatonin; prostate cancer

PMID: 27736013 DOI: 10.1111/jpi.12373

[PubMed - as supplied by publisher]

[Neal-Snyder]

Hi Patrick,

Of course I'm glad to hear that. However, I can't tell if it speaks to whether my current bedtime dose of 20 mg (which I got from some other study) is optimal or not. Is there anything here that gives you a clue about what's a good dosage?

And I'll ask a possibly stupid question I've had for a long time. When a report like this refers to "the prostate," & I had a RP, how if at all does that effect its relevance to me & the other guys who left their prostate in the OR?

Thanks,

Neal

[pjoshea13 in reply to Neal-Snyder]

Neal,

Cancer studies have used 10, 20, 40 & 50mg, but there is nothing useful that points to 50 versus 40 (the old LEF number) - or 40 versus 20 - in PCa.

When I had my RP 12 years ago, I was warned that I would be stapled back up if pathology found cancer in the lymph nodes. In fact, that was the fate of the afternoon patient, who had "far less cancer".

These days, I read of the benefit of RP in cases that are unlikely to be organ-confined.

While it's nice to see studies with result breakdowns by diagnosis/treatment/etc, I find them all useful.

-Patrick

[Neal-Snyder in reply to pjoshea13]

Thanks, Patrick.

My RP was 13 years ago, & they went ahead despite the micro-metastases to the pelvic lymph nodes. They also found capsular penetration.

I went to the Prostate Cancer Research Institute annual conference in LA last month, on Chuck Maack's excellent recommendation. They were all for "debulking" in guys with advanced PC who hadn't had RPs.

My 2nd question wasn't clear. If a report says, e.g., "The prostate is a well-known target for melatonin," & most of us don't have one, how do we read that? Is it the prostate bed that's still a target for melatonin, or circulating PC cells, or what? Seems like supplements that are relevant when we have prostates remain so for advanced PC patients, right?

[pjoshea13 in reply to Neal-Snyder]

To the extent that PCa cells act like normal prostatic epithelial cells, one would expect benefit.

An exception is zinc, where PCa cells inhibit production of the transporters that bring zinc into the cells.

In the case of melatonin, pineal gland production seems to be lowered, but there doesn't seem to be local interference. It is possible, though, that after a period of high supplementation, PCa might find a way to block uptake.

Sadly, if a therapeutic agent is initially successful, we either eradicate the cancer or select for cells that are resistant.

-Patrick

[Darryl Partner]

Super interesting. Is this sufficient to have us consider melatonin supliments?

[Charlean in reply to Darryl]

The good thing is, I don't think it will harm you so why not just try it?

Charlean

[pjoshea13 in reply to Darryl]

Hi Darryl,

See my new post:

"Foods/Supplements-Vitamins: Melatonin"

-Patrick

[Hidden]

Patrick, I continue to be very impressed and grateful for your numerous posts. I am curious. Do you have a medical or scientific / engineering background?

[pjoshea13 in reply to Hidden]

I designed & built systems in the actuarial field. Retired early & got PCa early, so had plenty of time to devote to PubMed.

It didn't take long to get used to the jargon. Most scientific papers are surprisingly well-written. Some of the foreign language papers are poorly translated, but one can usually figure out was intended.

PCa is a very large topic compared to 12 years ago. 158,539 Pubmed hits for <prostate> this morning. I was lucky to start when I did. LOL

-Patrick