Melatonin impedes prostate cancer metastasis by suppressing MMP-13 expression

[pjoshea13]

New study below [1].

The MMP (matrix metalloproteinase / metallopeptidase) family break down the matrix that holds cells in place. MMPs are elevated in cancer & facilitate metastasis.

If this were only another cell study I might have hesitated to post. But:

"PC3‐Luc cells were injected into SCID mouse prostates .... We found that three times weekly administration of melatonin (20–60 mg/kg) concentration‐dependently inhibited prostate cancer development ... Importantly, melatonin suppressed the metastasis of prostate cancer to distant organs, including the lung, liver, and bone ... To validate the molecular target in melatonin‐treated cells, we conducted an IHC analysis of prostate tumor specimens. The results revealed that melatonin markedly inhibited the expression of MMP‐13 ... Hematoxylineosin staining confirmed that melatonin markedly reduced the metastasis of prostate cancer to the lung, liver, and bone ... Based on these findings, we propose that melatonin impedes in vivo metastasis by suppressing MMP‐13 expression in human prostate cancer."

OK, so you are looking at that 20–60 mg/kg dosage, rapidly converting lbs to kgs & coming up with an impossible dose, but the result is intriguing.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/332...

J Cell Physiol

. 2020 Nov 29. doi: 10.1002/jcp.30150. Online ahead of print.

Melatonin impedes prostate cancer metastasis by suppressing MMP-13 expression

Shih-Wei Wang 1 2 , Huai-Ching Tai 3 4 , Chih-Hsin Tang 5 6 7 , Liang-Wei Lin 1 5 , Tien-Huang Lin 8 9 , An-Chen Chang 5 , Po-Chun Chen 10 , Yi-Hsuan Chen 1 11 , Po-Chuan Wang 12 , Yu-Wei Lai 13 14 , Shiou-Sheng Chen 14 15 16

Affiliations collapse

Affiliations

1 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.

2 Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.

3 School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.

4 Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan.

5 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.

6 Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.

7 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.

8 Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan.

9 School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan.

10 Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.

11 Department of Urology, MacKay Memorial Hospital, Taipei, Taiwan.

12 Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan.

13 Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan.

14 Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan.

15 Division of Urology, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan.

16 Commission for General Education, College of Applied Science, National Taiwan University of Science and Technology, Taipei, Taiwan.

PMID: 33251599 DOI: 10.1002/jcp.30150

Abstract

Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP-13) expression are higher in prostate cancer patients than in healthy cancer-free individuals. Mechanistic investigations revealed that melatonin inhibits MMP-13 expression and the migratory and invasive capacities of prostate cancer cells via the MT1 receptor and the phospholipase C, p38, and c-Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP-13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations.

Keywords: MMP-13; MT1 receptor; melatonin; metastasis; prostate cancer.

© 2020 Wiley Periodicals LLC.

[cigafred]

Did the mice ever wake up?

[Garp41]

fullscript.com/blog/how-mel...

This article says 5mg/day had some effect.

Doug

[mperloe in reply to Garp41]

But the mice weight much less than a kg.

[snoraste]

Dosage is a big question. I don't see the full article, but I'm reading it as 20-60mg/kg (~ 9-27mg/lb) each dose, 3 times a week. I have increased my dosage from 20mg/day to 180mg/day over a 4 month period (gradually) with no side effects which puts me on the lower end of this range. I know people who take 1.5x my dosage with no issues, and I also know that there are benefits to it at much lower dose. This study seems to suggest a dose-dependent benefit at these higher doses. Perhaps Melatonin has a "J" curve and its mechanism of action changes at higher concentrations?

[Ralph1966 in reply to snoraste]

Are you taking tablets/capsules or using bulk powder Melatonin? Which brand if you don't mind to share?

[Kentucky1 in reply to Ralph1966]

Largest dose that I've found is 60mg, called Melatonin Max from Perfect Vitamins

[snoraste in reply to Ralph1966]

I’m taking Melatonin Max.

[podsart in reply to snoraste]

Dosage in all these studies seems always an issue in addition to mice to human conversion. I find it interesting to read about the high doses some of us are taking, seemingly with no ill effects. I was instructed by Dr Myers to take 2 x 3mg time release melatonin (life extension) pills per day. I have been doing so for years. I remember when I reported to him I was taking a bit higher level, as I believed that was the dosage ( I thought ) he told me to originally take-had no ill effects from that dosage, that I could tell. He told me “no, reduce to the 2 pills per day”, as I am on now, as it wasn’t good to be on that somewhat higher dose.

I am reading about these much higher doses and am confused. He was the only Dr I know who involved himself seriously and knowledgeably in these supplement issues.

[Hidden]

I was about to note the dosage but, before I posted, read the rest of your post. Be nice if they used realistic doses in their experiments. A range would be good so that we might have an idea of how to view other studies. For this one, 1mg/kg to 20mg/kg.

[Hidden]

Thanks . I’ve taken 20 mgs nightly for over five years .. per my Nat onco ..He knows his stuff...

[ctflatlander in reply to Hidden]

Scott. Did you work your way up to 20 mg/day and what brand did your onc recommend? Thank you

[jdm3 in reply to ctflatlander]

Like Scott, my brother from a different mother, I take 20 mg too. Pure Encapsulations brand. Also recommended by naturopathic oncologist.

[Hidden in reply to jdm3]

Bueno! 💪🏼

[Seebs9 in reply to jdm3]

Thats Brotha from anotha mutha

[Hidden in reply to ctflatlander]

No ,I went straight to 20 mgs ,accompanied by low dose naltrexone 4.5 .

[drmoose]

There is a reference to "dose conversion" between animal models and humans dx.doi.org/10.4103%2F0976-0... that suggests to convert from mice to men, divide by 12.3 for the mg/kg dose.

So if that is correct - I am 80 kg, the range would be 130 mg to 390 mg per day, which seems just a little less crazy 🤔

[drmoose in reply to drmoose]

better link: ncbi.nlm.nih.gov/pmc/articl...

[mperloe in reply to drmoose]

Not sure why you would reduce the mg/kg dose?

[drmoose in reply to mperloe]

I would suggest reading Steinbeck to investigate why the dosages of mice and men are not quite yet the same 😉

[Newyork6264]

Interesting information. I’m presently doing chemo (Taxtore). Does anyone know if you can take Melatonin while on chemo?

[45yrsDenmark]

1) Can anyone recommend how to increase the dose when you start from zero? would it be 2 weeks with 3mg, 2 weeks using 5mg, 2 weeks using 15mg etc.. or is that too fast? Any proposals?

2) What would be the target dose? 60mg once per day maybe?

3) What brands is favorable? I live in Denmark, and here it is not a supplement, but a prescribed drug, so I would need to purchase online and hope the customs don't discover it...

Thanks

[Hidden in reply to 45yrsDenmark]

My nat oncologist put me on 20 straight off .. I would start there . No need to dose up .

[Ausi in reply to 45yrsDenmark]

A few weeks ago I started on 10mg then upped it to 20mg 3 days later. I got dizziness in the morning. Apparently it is a side effect, I’ve dropped back to 5mg but have now upped it to 10mg. Has anyone else had this side effect and does it go away?

[Justfor_ in reply to Ausi]

I started with 1 mgr pills. Before the week was over I was taking two of these. When the bottle got empty I continued with 5mgr pills. Same story, soon enough taking two of these until the bottle got empty. Next bottle of 10mgr pills, this time sublingual. Took them for a number of months until read here that people are doing double that. So, two 10mgr pills for me as well, but with a twist. I take one just before going to bed and the second during the nightly visit to the toilet along with nattokinase. No SE whatsoever.

[Shooter1 in reply to Justfor_]

Same sort of progression. 10./20./24/30/35/and now 40. 30 before bed, 5X2 at night. No grogginess, no hangover. Doing any good?? Who knows.Doug .

[cigafred in reply to Justfor_]

Does the melatonin mean that the nattokinase is not being taken on an empty stomach? It would help me a lot if it is ok to combine these two.

[Justfor_ in reply to cigafred]

I can't really answer your query. I was taking the Nattokinase in the middle of the night being on an empty stomach. I read about this arrangement here and have been following it since then. Lately, I have added the second melatonin pill with it (always in the middle of the night) without knowing if there is any interaction between the two.

[pjoshea13 in reply to cigafred]

I have been taking nattokinase & melatonin just before bed for years now. For me, "empty stomach" means that the last meal has been digested. I also take Simvastatin, Avodart, Iodoral, Magnesium & Relora before bed.

-Patrick

[cigafred in reply to pjoshea13]

Thank you Patrick and Justfor

[Justfor_ in reply to pjoshea13]

Thanks Patrick. I also take my statin, along with the first melatonin pill, when going to bed. I have scheduled Avodart with breakfast. Is there any benefit in taking it at bedtime? TIA

[pjoshea13 in reply to Justfor_]

Not that I know of. Other than you sleep through any side-effects.

[j-o-h-n]

Melatonin? I think I've heard that word before.....

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 12/06/2020 11:33 PM EST

[mperloe]

3/4 pound should not be that difficult. 😃

[PhilipSZacarias]

Hello Patrick, The calculated equivalent dosage, when converting from a mouse dosage rate to human, the dosages of 20 to 60 mg/kg converts to 118 to 353 mg for a 160 lb person - quite high. I have not been able to obtain a copy of the paper yet. Cheers, Phil

[pjoshea13 in reply to PhilipSZacarias]

Phil,

I expect that humans approach saturation level at much lower doses. I wonder how that might be tested?

A number of non-PCa studies have used 20 mg. If any one of them had also tested with 30, 40, 50 mg, we might have had a clue.

Hope you are well, -Patrick

[PhilipSZacarias in reply to pjoshea13]

Hello Patrick, I found the following paper which may be of interest: pubmed.ncbi.nlm.nih.gov/260...

After HIFU (for the recurrence in the prostate) and SBRT to T12 I am in a wait-and-see mode while on abiraterone (PSA ~0.17 ng/ml). Otherwise enjoying life despite SARS-COV2. Cheers, Phil

[pjoshea13 in reply to PhilipSZacarias]

Thanks Phil,

Here is the full text of the 100mg study:

sci-hub.do/10.1016/0024-320...

-Patrick