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Advanced Prostate Cancer
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Melatonin - Review.

New review paper from Spain below.

I have been using melatonin for PCa for 15 years. Initially at 40 mg before bed; ultimately at 50 mg as per change in LEF recommendation. But not before I reviewed the literature.

This is the PCa section:

"3. Melatonin and Hormone-Dependent Prostate Cancer

Prostate cancer (PC) is one of the leading causes of death by cancer among males in the developed world. As prostate physiology is under the control of androgens (testosterone and dihydrotestosterone) and their metabolites, androgen deprivation therapy (by inhibition of hormone biosynthesis or androgen receptor deprivation) has been extensively used in PC. However, most patients will develop hormone-refractory cancer [68]. As well as in the case of the mammary gland, the role of melatonin in the prostate has been established a long time ago. In vivo, melatonin (at a pharmacological dose of 150 mg/100 g of body weight, administered for 4 weeks) induced a significant decrease in the ventral prostate weight in castrated and castrated-testosterone-treated rats [69]. Conversely, pinealectomy was effective in stimulating androstenedione and testosterone production indicating an inhibitory action of the pineal gland on testicular steroidogenesis in rats [70]. Shortly after these findings, the involvement of melatonin in prostate cancer was unrevealed. In humans (patients with nonmetastasizing carcinoma), the pineal hormone did not show significant circadian rhythms indicating that the modulation of melatonin plasma levels might be related to prostate cancer genesis and growth [71]. Because of the antigonadotropic effect of melatonin, the hypothesis that the pineal hormone could inhibit prostate cancer was tested in vivo in rat prostatic adenocarcinoma. The main conclusion was that melatonin (50 μg/rat, daily injected one hour before darkness) suppressed the growth of prostate tumors [72]. Back to humans, when the circadian rhythms of melatonin and 6-sulfatoxymelatonin were analyzed in the serum of elder patients with primary prostate cancer, a reduced pineal activity was found [73]. Also in humans, a clinical combination of melatonin and the LHRH analogue triptorelin was tested in metastatic prostate cancer patients with promising results. The concomitant administration of melatonin (a therapeutic dose, orally administered at 20 mg/day, in the evening every day until progression, starting 7 days prior to triptorelin) may overcome the resistance to LHRH analogues and palliate the adverse side effects [74]. According to these results, a physiological dose of melatonin (1 nM) attenuated the growth of the human androgen-sensitive prostatic tumor cell line LNCaP in vitro [75]. The expression of the membrane Mel1a melatonin receptor was demonstrated in this cell line, and an accumulation of the cells in G0/G1 and a decrease in S phase were obtained by treatment with melatonin at nanomolar concentrations [76]. Interestingly, the direct oncostatic activity of melatonin (1 nM) was also demonstrated in vitro in human androgen-independent DU 145 prostate cancer cells. As occurred in breast cancer, the indoleamine caused cell-cycle withdrawal by accumulation of cells in G0/G1 and inhibition of cell proliferation [77]. Back to the androgen-responsive prostatic LNCaP cells, a melatonin-mediated nuclear exclusion of the androgen receptor (AR) was demonstrated, indicating that melatonin (used at concentrations ranging from 1 nM to 100 nM) might regulate AR activity [78]. At 100 nM, melatonin induced a rise in intracellular cGMP, leading to an increase in calcium levels and PKC activation [79]. In vivo experiments in rodents showed that epidermal growth factor (EGF) stimulated LNCaP tumor growth in nude mice and induced an increase in the levels of Cyclin D1, whereas melatonin (at a pharmacological dose of 4 mg/g of body weight, administered intraperitoneally 1 h before lighting was switched off) counteracted this effect [80]. An in vitro study evaluating the effect of melatonin in both androgen-dependent (LNCaP) and androgen-independent (PC3) cells demonstrated that treatment with the indoleamine (10 nM to 1 mM) dramatically reduced the number of both types of cells and, in addition, induced cellular differentiation. The effect of melatonin was not mediated by PKA although a transitory rise in cAMP levels was observed [81]. In androgen-dependent prostate cancer cells, it has been demonstrated that pharmacological doses of melatonin (ranging from 50 nM to 1 mM) increased p21 levels, decreased NF-κB activation, and Bcl-2 and survivin were downregulated [82]. The inhibition of NF-κB signaling via melatonin-dependent activation (melatonin dose: 10 nM) of PKA and PKC resulted in transcriptional upregulation of p27 (Kip1), a MT1-dependent antiproliferative signaling mechanism [83]. In LNCaP cells, the pineal hormone (at different concentrations from 0–3 mM) induced both early and late apoptosis, both dependent of activation of c-JUN kinase (JNK) and p38 kinase, strongly suggesting that these kinases directly participate in apoptosis triggered by melatonin [84]. In androgen-dependent but also in androgen-independent prostate cancer cell lines, melatonin (1 mM) seemed to exert an antiangiogenic effect since it reduced hypoxia-inducible factor (HIF-1) protein levels and the release of the vascular endothelial growth factor, which correlated with dephosphorylation of p70S6 kinase and its target, ribosomal protein RPS6 [85]. In prostate cancer cell lines (in vitro) and transgenic adenocarcinoma or mouse prostate (TRAMP) mice (in vivo), melatonin (dose: 10–20 mg/l in drinking water, for 18 weeks) inhibited tumorigenesis by decreasing the serum levels of IGF-1, IGFBP3, and proliferation markers such as PCNA and Ki-67. Sirt1, a NAD(+)-dependent histone deacetylase overexpressed in prostate cancer, was also inhibited by melatonin in correlation to a significant antiproliferative effect [86]. In vitro, in both androgen-sensitive LNCaP and insensitive PC-3 cell lines, the pineal hormone (1 mM) limited glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathways, indicating that melatonin slows down glucose metabolism in both prostate cancer cell lines [87]. Yet more molecular mechanisms have been recently characterized in vitro (prostate cancer cell lines) and in vivo (TRAMP mice models). KLK2, KLK3 (kallikreins), and IGF1R were downregulated, whereas IGFBP3 was upregulated by melatonin (pharmacological doses: 10–20 mg/l in drinking water, for 18 weeks), demonstrating the role of the IGF signaling pathways in the oncostatic effect of the pineal hormone [88]. Additionally, an increase in phosphorylation of Akt in melatonin-treated (dose: 18 i.p. injections at 1 mg/kg of body weight, treatment lasting for 41 days) nude mice in which LNCaP cells were xenografted has been demonstrated in vivo [89]. Recent evidence suggests that microRNAs (miRNAs) are good candidates to be considered as targets in cancer treatments. In androgen insensitive PC-3 lines subjected to hypoxia, melatonin (1 mM) upregulated miRNA3195 and miRNA374b. Overexpression of miRNA3195 and miRNA374b decreased the levels of the proangiogenic proteins VEGF, HIF-1, and HIF-2, thus explaining, at least in part, the antiangiogenic properties of melatonin in prostate cancer [90]. It is widely accepted that desynchronization of the clock circuitry after alterations in the circadian rhythms is implicated in cancer. Indeed, melatonin (100 μM to 2 mM) increased the levels of Per2 and Clock, whereas reduced Bmal1 in prostate cancer cells [91]. Combined with chemotherapeutic agents (etoposide, doxorubicin, or docetaxel), melatonin (1 mM) enhanced the sensitivity of cancer cells to cytokine-induced apoptosis in vitro [92].

"As in breast cancer, some attention has been drowned into the hypothesis that light-at-night (LAN) exposure can inhibit nocturnal melatonin, and consequently, prostate cancer risk would be elevated. The countries with higher levels of nocturnal light yielded a higher risk of prostate cancer [93]. Men who never worked at night in night-shift turns have a lower risk of prostate cancer in comparison with night-shift workers [94]. Men who reported sleep problems had lower morning levels of urinary 6-sulfatoxymelatonin in association with an increased prostate cancer risk [95]. Aggregate genetic variation in melatonin and circadian rhythms were also significantly associated with the risk of prostate cancer, but no significant association could be established for lung and ovarian cancer, supporting a potential role of melatonin pathways and circadian rhythms in prostate carcinogenesis [96]."

-Patrick

Full Text: hindawi.com/journals/ije/20...

Abstract: ncbi.nlm.nih.gov/pubmed/303...

Int J Endocrinol. 2018 Oct 2;2018:3271948. doi: 10.1155/2018/3271948. eCollection 2018.

Melatonin: An Anti-Tumor Agent in Hormone-Dependent Cancers.

Menéndez-Menéndez J1, Martínez-Campa C1.

Author information

1

Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain.

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland mainly during the night, since light exposure suppresses its production. Initially, an implication of this indoleamine in malignant disease was described in endocrine-responsive breast cancer. Data from several clinical trials and multiple experimental studies performed both in vivo and in vitro have documented that the pineal hormone inhibits endocrine-dependent mammary tumors by interfering with the estrogen signaling-mediated transcription, therefore behaving as a selective estrogen receptor modulator (SERM). Additionally, melatonin regulates the production of estradiol through the control of the enzymes involved in its synthesis, acting as a selective estrogen enzyme modulator (SEEM). Many more mechanisms have been proposed during the past few years, including signaling triggered after activation of the membrane melatonin receptors MT-1 and MT-2, or else intracellular actions targeting molecules such as calmodulin, or binding intranuclear receptors. Similar results have been obtained in prostate (regulation of enzymes involved in androgen synthesis and modulation of androgen receptor levels and activity) and ovary cancer. Thus, tumor metabolism, gene expression, or epigenetic modifications are modulated, cell growth is impaired and angiogenesis and metastasis are inhibited. In the last decade, many more reports have demonstrated that melatonin is a promising adjuvant molecule with many potential beneficial consequences when included in chemotherapy or radiotherapy protocols designed to treat endocrine-responsive tumors. Therefore, in this state-of-the-art review, we aim to compile the knowledge about the oncostatic actions of the indoleamine in hormone-dependent tumors, and the latest findings concerning melatonin actions when administered in combination with radio- or chemotherapy in breast, prostate, and ovary cancers. As melatonin has no toxicity, it may be well deserve to be considered as an endogenously generated agent helpful in cancer prevention and treatment.

PMID: 30386380 PMCID: PMC6189685 DOI: 10.1155/2018/3271948

36 Replies
oldestnewest

Melatonin is one of more researched over the counter supplements. Italy and Spaineading the way. Sadly very few large scale trials are done on natural stbstances/protocols in the US. It IS about $. If not patentable, no interest.

I used 20 mgs daily (nightly) for years.

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Is there any other research about Melatonin and prostate cancer that you are aware of?

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I have two old posts (2+ years):

healthunlocked.com/advanced...

healthunlocked.com/advanced...

{I am disappointed to see "dissapointed" in this post.}

I will be posting on a more recent study.

-Patrick

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ncbi.nlm.nih.gov/pubmed/?te... From the National Library of Medicine online (accessible at pubmed.gov). I did the search for you.

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2. Melatonin

Researchers are waking up to the fact that people whose bodies produce more melatonin are more cancer resistant. And they are also finding that, in many cases, giving cancer patients melatonin supplements when they’re being treated increases their chance of surviving and eradicating their tumors. For instance, a study at the Harvard School of Public Health shows that men with a higher level of melatonin circulating in their blood run a reduced risk of developing advanced prostate cancer.1 Researchers at the Tulane University School of Medicine conducted a laboratory study of how breast cancer cells react to tamoxifen – an anti-cancer drug first discovered in the late 1960s. Tamoxifen is still the most frequently used drug that’s given to breast cancer patients.2 The researchers found that exposure to light at night – which is known to hamper the body’s production of melatonin -- can make breast cancer completely resistant to treatment with tamoxifen.

However, the tests on animals showed that melatonin supplementation, even if the animals didn’t have much melatonin in their bodies (because they were exposed to light at night), could, by itself, without anti-cancer drugs, slow the growth and formation of breast tumors. The lab experiments also demonstrated that melatonin supplements given to melatonin-deficient animals made tamoxifen much more effective at eradicating tumors. According to researcher David Blask, who is with Tulane's Circadian Cancer Biology Group, "High melatonin levels at night put breast cancer cells to 'sleep' by turning off key growth mechanisms. These cells are vulnerable to tamoxifen. But when the lights are on and melatonin production is suppressed, breast cancer cells 'wake up' and ignore tamoxifen.”

In a study of breast cancer patients being treated with tamoxifen, researchers found that adding melatonin to the regimen made the tamoxifen so much more powerful, it was possible to reduce the dose of the drug

without a loss of effectiveness.3 Being able to use a lower dose of tamoxifen is important because the drug, especially in large amounts, can cause serious and even deadly side effects: It can increase the chances of stroke, uterine cancer, vision difficulties and pulmonary embolism. It can also lead to hot

flushes, weight loss and irregular menstruation. In addition, during cancer treatment, cancer cells may grow resistant to tamoxifen, rendering it less effective. Eventually, the cancer cells can resist the drug entirely and keep forming larger tumors.

Building on the research that shows melatonin boosts apoptosis (the process that leads cancer cells to engage in a type of suicide) these researchers believed the hormone could make tamoxifen more deadly to cancer cells and render those cells less likely to develop resistance. And the study confirmed that it does. In this test, cancer patients received their melatonin within an injection of small bubbles called nanostructured lipid carriers (NLCs). These are designed to provide a time-released dose of melatonin gradually, over a prolonged period of time. Going along with these results, a study at the University of Colorado Cancer Center showed that melatonin can be helpful in fighting malignant melanoma, a form of skin cancer that can be life-threatening.5

Take 10 mg a day, at bed time. Ideally mix the melatonin in some whole milk or ½ -and -½ taking it since this will hugely increase its absorption – it is a fat soluble supplement. Swanson has a product, #SWU305, a 10 mg capsule, $5.99 for 60 capsules. Take 1 at bed time. A bottle will last two months.

References

1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318783/

2 ncbi.nlm.nih.gov/pubmed/250...

3 ncbi.nlm.nih.gov/pubmed/271...

4 ncbi.nlm.nih.gov/pubmed/181...

5 ncbi.nlm.nih.gov/pubmed/182...

6 mayoclinic.org/drugs-supple...

7 umm.edu/health/medical/altm...

8 umm.edu/health/medical/altm...

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Me too!

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This is new to me -- thank you. I do use melatonin, but I find that much over about 6 mg leads to pretty wild dreams.

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Many people say that they do not remember their dreams. Melatonin tends to make people more aware of them as they occur. Not always a good thing! Does it actually affect dream progression? Maybe not, but who can say?

-Patrick

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I use 20.. I dream a lot..some wild..

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My husband was taking melatonin at bedtime. Our integrative doctor is concerned about the contamination of melatonin. It occurred some time ago.. he believes it is only a matter of time before it happens again. He told my husband to stop taking it. Here is a link to what I suppose is what he is talking about

mayoclinicproceedings.org/a...

Do any of you know of sources of supplements for it that are well tested so as to eliminate the risk of this ? I would like for my husband to start back up with it.

thanks a bunch!

Softwaremom

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In other words, the contamination of a batch of tryptophan 30 years ago is being used as evidence(?) that melatonin is another disaster waiting to happen?

It's true that supplements (which the FDA treats as foods) are poorly regulated. There are only a few companies that I trust. I have recently mentioned that zinc & cadmium are naturally found together & that some cheap brands have been selling zinc with unacceptable levels of cadmium. The brands to use are those that test for purity.

Nalakrats knows more about the business end than I do. He might have some idea of the risk we run.

Meanwhile, I will take my 50 mg of melatonin tonight.

Best, -Patrick

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Patrick - that sounds like a high dosage. I used to take 5mg to help me with my sleep. Do you have any sleep related side effects?

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I long ago found that I sleep in ~2 hour cycles. Nothing can wake me during the first. I generally need a pee before the 2nd (thanks to the RP) & generally fall quickly back to sleep. The third can be problematic, since I often feel rested. If I do sleep, I often skip the 4th. In any case, my 4th is an in-&-out kind of sleep.

I'm quite happy with that. I'm usually up by 5:15 a.m. & fully alert even before the coffee. I don't understand the warnings about sleepiness the next morning.

Note that melatonin is an endocrine hormone with no feedback loop. That's because light & its absence control production. However, sensitive tissues have a nice control mechanism. The melatin receptor loses its sensitivity to it after exposure. By the time the night ends, circulating melatonin has totally lost its power - the targets have become numb to it. During the day, residual melatonin is cleared & the receptors regain sensitivity. It's obvious that supplementing during the day is counter-productive.

-Patrick

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Thanks - perhaps I’ll give it a try. Any particular formulation/manufacturer you recommend?

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I generally use the LEF product but have used the cheaper Swanson too:

lifeextension.com/Vitamins-...

swansonvitamins.com/swanson...

-Patrick

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Wow! I ‘ve used 20mg per night for four years. Do you recommended 40?

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The human studies tend to use 20 mg.

LEF says 50 mg is better for cancer.

-Patrick

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Thanks Patrick..

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why is mainstream medicine, e.g, my MO, not in favor of melatonin....or others?

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I will be increasing melatonin from 10 to 20mg, at night. and increasing coffee from 2 to 3 cups the next day!!!

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Turns out that coffee is associated with better PCa survival too! -Patrick

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Now you are talking.

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Funny!😴

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I am hearing 5mg, 10mg, 20mg, and 40mg.

How close to going to bed do people take it?

How fast does it get into your system on an empty stomach?

How about with a meal?

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For nearly four years I’ve taken 20 mgs. An hour before bed at night..I’m thinking about 40 now.. For me it’s good with or without food .. My naturalpathic put me on this . Says it fights cancer.. It helps sleep and that ain’t bad either. Also prescribed me naltrexone 4.5 low dose with the melatonin before bed..

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My Naturopath is far more conservative. He suggested 5mgs (which I take), but with a suggestion that every 2-3 months take a Melatonin holiday for 10 days, just so that your body does not give up producing the hormone altogether! Interesting viewpoint.

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As I mentioned elsewhere, there is no feedback loop to the pineal gland. I.e. it cannot respond to existing melatonin in the body. It responds only to a circadian absence of light. IMO, a holiday is unnecessary.

The only feedback to the pineal that we should be concerned with is premature exposure to light. Those who make an early trip to the bathroom for a pee & put a light on will cause melatonin production to immediately halt.

Along with that, one should avoid exposure to light from outside (street lights, etc.) & in the bedroom. Low level exposure to night lights might be ok but it depends on which end of the spectrum is emitted.

-Patrick

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Thanks Patrick. Excellent practical advice as ever.

Funnily enough, re light exposure, we went down the route of going for almost total blackout at night other than a very weak red/orange extremely low wattage night light, positioned at floor level in an adjoining room, which gives us extremely subdued illumination to find the bathroom - without the need for any Melatonin destroying bright lights!

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Interesting to take a break.. I will look into that... Thank you..

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I always dream that I'm sleeping...

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 11/04/2018 1:55 PM EST

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If a married man is in the wilderness without his wife and he speaks , Is he still wrong?

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LOL....

Not if he's with his girlfriend...

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 11/04/2018 5:47 PM EST

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You’re always one step ahead of me.. hahaha😎

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Hopefully not when we're walking through land mines...

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 11/04/2018 6:22 PM EST

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Make that two!

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What a guy!

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