"Advanced prostate cancer often develops into bone metastasis, which is characterized by aberrant bone formation with chronic pain and lower chances of survival. No treatment exists as yet for osteoblastic bone metastasis in prostate cancer.
"... melatonin ... is a major regulator of the circadian rhythm. Melatonin has shown antiproliferative and antimetastatic activities, but has not yet been shown to be active in osteoblastic bone lesions of prostate cancer.
"Our study investigations reveal that melatonin concentration-dependently decreases the migratory and invasive abilities of two osteoblastic prostate cancer cell lines by inhibiting FAK, c-Src and NF-κB transcriptional activity via the melatonin MT1 receptor, which effectively inhibits integrin α2 β1 expression. Melatonin therapy appears to offer therapeutic possibilities for reducing osteoblastic bone lesions in prostate cancer."
. 2022 Feb 16. doi: 10.1111/jpi.12793. Online ahead of print.
Melatonin suppresses the metastatic potential of osteoblastic prostate cancers by inhibiting integrin α 2 β 1 expression
Huai-Ching Tai 1 2 , Shih-Wei Wang 3 4 5 , Sanskruti Swain 6 , Liang-Wei Lin 7 , Hsiao-Chi Tsai 8 9 , Shan-Chi Liu 10 , Hsi-Chin Wu 10 11 12 , Jeng-Hung Guo 7 13 , Chun-Lin Liu 7 13 , Yu-Wei Lai 14 15 , Tien-Huang Lin 16 17 , Shun-Fa Yang 18 19 , Chih-Hsin Tang 6 7 8 20 21
Affiliations collapse
Affiliations
1 School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
2 Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan.
3 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
4 Institute of Biomedical Sciences, Mackay Medical College, Taipei, Taiwan.
5 Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
6 International Master Program of Biomedical Sciences, China Medical University, Taichung, Taiwan.
7 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
8 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
9 Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
10 Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin, Taiwan.
11 Department of Urology, China Medical University Hospital, Taichung, Taiwan.
12 Department of Urology, China Medical University Beigang Hospital, Beigang, Yunlin, Taiwan.
13 Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan.
14 Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan.
15 Department of Urology, College of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
16 Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan.
17 School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan.
18 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
19 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
20 Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
21 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
PMID: 35174530 DOI: 10.1111/jpi.12793
Abstract
Advanced prostate cancer often develops into bone metastasis, which is characterized by aberrant bone formation with chronic pain and lower chances of survival. No treatment exists as yet for osteoblastic bone metastasis in prostate cancer. The indolamine melatonin (N-acetyl-5-methoxytryptamine) is a major regulator of the circadian rhythm. Melatonin has shown antiproliferative and antimetastatic activities, but has not yet been shown to be active in osteoblastic bone lesions of prostate cancer. Our study investigations reveal that melatonin concentration-dependently decreases the migratory and invasive abilities of two osteoblastic prostate cancer cell lines by inhibiting FAK, c-Src and NF-κB transcriptional activity via the melatonin MT1 receptor, which effectively inhibits integrin α2 β1 expression. Melatonin therapy appears to offer therapeutic possibilities for reducing osteoblastic bone lesions in prostate cancer. This article is protected by copyright. All rights reserved.
Keywords: Bone metastasis; Integrin; MT1 receptor; Melatonin; Osteoblastic prostate cancer.
This article is protected by copyright. All rights reserved.
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pjoshea13
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He is talking about LDN, Low Dose Naltrexone. I also took it at some point, but I read somewhere that it can only be effective prior to initiating ADT and drop it.
Background: The antitumor and immunomodulating activities of melatonin are widely known. These activities are based upon the multifactorial mechanism of action on various links of carcinogenesis. In the present paper, the long-term results of the clinical use of melatonin in the combined treatment of patients with prostate cancer of various risk groups were evaluated.
Materials and methods: A retrospective study included 955 patients of various stages of prostate cancer (PCa) who received combined hormone radiation treatment from 2000 to 2019. Comprehensive statistical methods were used to analyze the overall survival rate of PCa patients treated with melatonin in various prognosis groups.
Results: The overall survival rate of PCa patients with favorable and intermediate prognoses treated or not treated with melatonin was not statistically significantly different. In the poor prognosis group, the median overall survival in patients taking the drug was 153.5 months versus 64.0 months in patients not using it (p < 0.0001). The 5-year overall survival rates in the research and control groups were 66.8 ± 1.9 and 53.7 ± 2.6 (p < 0.0001) respectively. In a multivariate analysis, melatonin administration proved to be an independent prognostic factor and reduced the risk of death of PCa patients by more than twice (p < 0.0001).
Conclusions: The multicomponent antitumor effect of melatonin is fully realized and clearly demonstrated in treatment of PCa patients with poor prognosis with a set of unfavorable factors of the tumor progression.
great info Thanks, I have been taking 3 mg, clearly not enough to make a difference. The highest dose I could find on Amazon is 20 mg, what is your source?
I was taking for many years 5mg just to sleep, after I read about anticancer properties I start taking 20mg, then 40-60mg... now reading this thread may think about going to 180mg or more 🤷♂️
A bit more stronger sleep and need less hours of total sleep to feel rested. Normally or with 3-5mg melatonin I need 8-9 hours to feel rested in the morning. with 40-60 mg - 7 hours generally is enough.
I purposely skip a night in approximately 10 days and sleep without melatonin... not to loose the ability to sleep without it😉
Thank you, I see that sex is important to you too and you considering external radiation - analyze carefully possible side effects. As you are doing great with hormone treatments, consider Lu-177 for "second strike" approach either through trial for mHSPC or in India, Europe etc... it is no way a SOC option and you need to weight your priorities.
Can you explain what lu177 is? I’ve looked it up without a lot of success understanding it. It can be combined with hormone therapy if someone is responding to hormone therapy? And if so how does one go about getting it? Thank you in advance for any time you can give to my question.
Hi, I recommend you do a search in this forum about Lu-177 to get some ideas browsing through corresponding treads.
It can be combined with hormone therapy for hormone sensitive cancer.
For hormone sensitive is available either through trials or out of pocket in Austria (most expensive), Finland (expensive), Azerbaijan (cheaper) and India cheapest option (but still very good option). Prices for one treatment between these options will be in range from 6.5K USD to 20,000 Euro plus fees for additional scans.
If you have specific questions about Lu-177 or about specific country to go for such treatment, I suggest you fully feel your profile with your father diagnoses and past current treatments and PSA and scans results and then start a new tread where you will get great input from many members.
I'm hormone sensitive and going to Austria to get my first treatment in a week time.
Thank you for that thoughtful reply. I’m hoping to get more information next week about my dad and then I will definitely fill out my profile. His diagnosis is fairly new and we don’t know how he is going to respond to treatment yet.
But one more question, to get those doses you have to leave the US each time or can they send it/administer it here for out of pocket?
You need to travel to these countries for these treatments. Another country I forgot to mention is Thailand. You may travel for each infusion, generally you need 2-3 of them or go and spend 3 months for example in Thailand (Like member of this forum "Bangkok" did).
One more question about dosing, as a follow up to that about determining a good anti-PC dose: should one start at that high dose, or work up to it, and is there optimal timing of single or multiple doses that has been theorized?
I found that even fairly smallish doses (1/2-5 mg) taken at 9-11 pm would cause vivid dreams(which I rather liked) but that I'd often pop wide awake between 2-4 am and have trouble getting back to sleep. Rather than a sleep aid, it was serving as a sleep disrupter.
I started at 40 mg 18 years ago - it was part of the LEF PCa protocol. Never had a problem & never noticed any effect on sleep. After a few years LEF raised the dose to 50 mg.
I'm inclined to think that if someone can tolerate 10 mg, say, 20-50 mg will not be a problem & titration will not be necessary. Those who have a problem with melatonin seem to do so at doses well below 10 mg. I'm intrigued that Devil Dog, who takes 180 mg, found a source for 60 mg caps. Have megadoses have become mainstream?
Patrick, I do not think they become mainstream - just some crazy people like few of us here and there taking them for problems more serious than trouble sleeping.
For 60mg I take Bella Phytologic , another option (I haven't try it, but may consider it to take them during the day) is Vitamatic Melatonin 60mg Fast Dissolve Tablets - 60 Vegan Natural Berry Flavor Tablets
Besides considering increase to 180 mg before sleep, after watching video provided by Teufelshunde - I will contemplate on taking melatonin during the day too (if it not make me sleepy during the day...)
I see Melatonin Max brand mentioned on other PCa forums. Many say they 240 mg or even more, often throughout the day, with no ill effects. I'm currently at 24 mg at nighttime only.
I had this problem of waking up at night after small doses of melatonin. Reasons mostly not melatonin in this case, but other type of stresses that bothering you. I was solving the issue by following up when I wake up in the middle of the night by taking another small dose and then I slept without issues. Higher doses starting from 30mg+ generally does not wake you up at night.
I take 180 mg before bed. Melatonin Max is 60mg each so I take three. I have auto ship from the manufacturer. Here is video where I first learned about melatonin. Worth a watch.
I watched it while burning off 500 calories on my indoor recumbent bike. Do you know the guy who was speaking- Shallenburger?
If half of what he claims is true it seems like a no brainer to be taking 360mg total all day and night at least every 4 hours if the half life is 5 hours
What else is available to us that will double the time to metastatic progression? Do I understand that correctly? Cheap , Well tolerated and no side effect?
I watched a little of it. I prefer to read articles because I can read faster than a guy can speak. The lecture was probably informative but an hour!
I heard the part about white blood cells in culture. I don't know if they also did human studies with various doses and timing schemes but petri dish experiments often miss the mark. For example no diurnal cycle in a petri dish. I don't recall the stats but it's something like 1 in 1000 petri dish studies translate to humans. 1 in 100 mouse studies.
I read an article somewhere about melatonin being a negative for cancer therapy if it is taken during the day. I didn't need much convincing since it seems like it would screw up your circadian rhythm. The doses I heard (60 mg 4+ times a day) are prooxidant. He mentioned antioxidants at the start of the lecture. I don't know if he clarified later. Much of the NIH research that I have read talks about the dose-dependant dual nature: antiox and pro-ox. I worked out the dose from 3 articles and the threshold varied from 3 to 6 mg. To be safe I set my own threshold for <1 mg antioxidant, >10 mg prooxidant. Between is a no-go zone for me.
Thanks for your thoughtful analysis, I really appreciate that you, Patrick and others have spent a lot of time thinking about all these alternative ideas to SOC. I know that I am standing on your shoulders with so much of this stuff and getting the benefit of your experience. I hope that at some point I can return the favor.In the mean time I just want to say THANKS for sharing your deep knowledge and resources.
Looks like Anti-cancer dose starts at minimum 20mg and I guess "sky is the limit", but interesting info about 180mg at nigh worth investigating at-least for me.
Where does anti-cancer starts at 20 mg and the skies the limit come from?The studies I've read use 3 and 5mg dosages. They also stopped supplementing during the spring and summer months since natural melatonin production increases.
Good question. I hope you get a response. Based on all this discussion I doubled my dose from 10 to 20 mg. before bed last night. I slept well but was feeling tired after breakfast and went back to sleep for over an hour which I attribute to the increased dose. I didn’t notice any effects with the 10mg. My wife’s doctor said take it earlier in the evening.
Hi, my guess that "sky is the limit" came from the information that none of the studies that I've encountered showed any serious side effects from any mega dose of melatonin.
Anecdotal evidence of some people regularly taking 180mg at nigh worth investigating at-least for me.
Here ncbi.nlm.nih.gov/labs/pmc/a... - you will find review of the studies almost all of them used 20mg, that is why it looks like reasonable minimum for anti-cancer properties is 20mg.
From the study you cited: "A dosing of 3 mg of melatonin thirty minutes before bedtime is appropriate for men with low-grade prostate cancer. Those with advanced prostate cancer may want to consider upping the dose to 20 mg. Both of these suggested dosages have proven to be safe in studies (Srinivasan et al. 2008). "
I agree, Sleep is extremely important and agree that there are no long term studies on the use of it, but taking into consideration that we have stage 4 cancer our goal should be what happen in the next 5 years... and then hopefully another 5 years, etc...
The article is a little confusing because it references several studies and the author adds in his own two cents based on several uncited studies. I believe the Iceland study used 5mg daily before bed. The 3mg was a nother study.
Melatonin might be useful for CRPC. It is antioxidant at low doses approx<7mg, pro-oxidant at high approx>7mg. What has come out from RCTs is that there is a very slight improvement in sleep.
Some links:Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy - PubMed
A Study of the Efficacy of Prolonged-Release Melatonin Versus Placebo in Diabetic Patients Suffering From Insomnia - Study Results - ClinicalTrials.gov
Sci-Hub | Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opinion on Therapeutic Targets, 17(12), 1483–1496 | 10.1517/14728222.2013.834890
Hi Art, I take 20mg a night when I am on the ADT cycle of BAT. If you take it, take it in the evening or before bed. Taking it other times messes with your circadian rhythm and some research shows that PCa can actually get worse if melatonin is taken during the day.
Russ, can you please point me to research regarding Melatonin during the day and PC?
Looks like Riordan clinic promoting melatonin 3-6 times a day for serious stage 4 patients, so I would like to see opposite research please… as I was considering to try it during the day.
Wow, great information. I'm just starting to learn about Melatonin so forgive me if this is a dumb question. My MO told me that antioxidants can actually promote growth in MPC tumors. She therefore told me to be careful with supplements. It sounds like higher dose Melatonin is pro-oxidant at higher levels and therefore would retard tumor growth. Is this the reason why you're recommending a higher dose? Thanks
Pretty much. It appears to me that antioxidants are beneficial to prevent cancer, but once it exists, they might not help.Caveat: The antioxidant theory makes sense but I haven't seen proof of this, mostly just somewhat stretching conclusions from trials and research.
Thanks Patrick . I’ve been taking 40 mg nightly for 12 years for my PCa . Maybe that’s why I don’t have bone Mets ( according to bone scan and PSMA - Pet ) even though my PSA got to 61 last summer before I got 26 sessions of radiation ( just finished Friday ) and started Orgovyx and Abiraterone with prednisone .
Thanks Patrick,Please Keep them coming. Wish. I could figure out a grading system like RSH1 for survival from most important to least important. I cannot keep adding everything that seems important, but this makes sense, and should help w sleep as a double benefit.
Thanks, Mike, send me a PM and I'll get some info to you. My scoring system is objective/subjective if that makes sense. But it is something that helps me reduce my drug burden. Melatonin is #13 on the list.
The relatively recent Russian study is an anomaly. Intervention studies have typically used 20 mg & sometimes more. I would not take less - but I have no idea what the optimum range would be.
Check that you take pure melatonin with no additives. Also make sure when you take it - you have minimum 8 hours to sleep, you may need less than 8 hours or more, but taking melatonin without enough time to rest can make you feel the way you described. Try it.
Unfortunately for small percentage of people melatonin might be not suitable at all and you migh be one of them🤷♂️
Melatonin is only available in the UK and I believe in Europe as a prescription 'medicine'. My GP has prescribed it ongoing, 2mg, as basically I have terminal cancer so he was not worried about addiction etc. but ordinarily it is only prescribed for a short time period. I am aware that some people might import Melatonin in a powder format. Are there any members who can recommend a good supplier of Melatonin in the UK, asking for a friend...
"while osteolytic components are present in both osteoblastic and osteolytic bone lesions, inhibition of the osteolytic component is not sufficient to alter the vicious cycle leading to tumors with an osteoblastic phenotype. These observations suggest that osteolytic and osteoblastic bone metastases are not the same and tumor-induced osteoblastic and osteolytic activity play different roles in supporting their growth and survival."
That like so much about our PCa cell activity is not yet fully understood. As goes for bone cancer tumors caused by our PCa.The proliferation of cells/tumors (we often refer to as progression) is complicated and again not completely understood.
We know bone tumors create their own environment to thrive, mutate, proliferate. Not sure why we should be confident that melatonin is the magic that can overcome millions of mutations that we don't fully understand.
This part of the quote related to that especially with:
inhibition of the osteolytic component is not sufficient to alter the vicious cycle leading to tumors with an osteoblastic phenotype.
All of us that have PCa in the bones are struggling to find the right meds, supplements or combination of the two that will buy us time. Of course melatonin is not a silver bullet to kill this beast otherwise we'd all be using it. For me the questions include, is there a reasonable chance it will slow down tumor growth? Could it hurt or cause cancer to grow faster? Are there significant side effects that would negate possible benefits? I'm still researching melatonin but in general I believe in throwing everything but the kitchen sink at this disease and being as aggressive as possible early on. Thanks for all of the comments and links!
Well that took me down a rabbit hole. Thanks for all the posts guys. Great info. I'd forgotten that I can't take melatonin. Years ago I tried it as a sleep aid and it gave me the Jimmy legs (aka restless leg syndrome).
If you have not watch the video that Teufelshunde posted, you should. It is worth your while. I watched it last night and the doctor has patient's taking melatonin during the day too.
I read an article today that talked about combining melatonin and DHA. Here is the quote:
"As Reiter et al. reported, proper use of melatonin combined with other oncostatic agents can enhance the therapeutic effect [207]. For instance, DHA, a fatty acid present in the human diet, can exert a pro-apoptotic effect against PCa cells via Akt-mTOR signaling."
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