Melatonin

New paper below.

See also my post of 6 months back:

"Foods/Supplements-Vitamins: Melatonin"

There seems to be a lack of interest in melatonin. I take 50 mg every night & am dissapointed in the paucity of papers. Here's an understatement from the new paper:

"Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level."

-Patrick

ncbi.nlm.nih.gov/pubmed/284...

Int J Mol Sci. 2017 Apr 17;18(4). pii: E843. doi: 10.3390/ijms18040843.

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis.

Reiter RJ1, Rosales-Corral SA2, Tan DX3, Acuna-Castroviejo D4, Qin L5, Yang SF6, Xu K7.

Author information

1

Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA. reiter@uthscsa.edu.

2

Centro de Investigacion Biomedica de Occidente, Del Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico. espiral17@gmail.com.

3

Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA. tan@uthscsa.edu.

4

Centro de Investigacion Biomedica, Universidad de Granada, Granada 18916, Spain. dacuna@ugr.es.

5

Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA. qinlilan1980@gmail.com.

6

Institute of Medicine, Chung Shan, Medical University, Taichung 40201, Taiwan. ysf@csmu.edu.tw.

7

Department of Molecular Medicine, UT Health, San Antonio, TX 78229, USA. xuk3@uthscsa.edu.

Abstract

There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin's co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.

KEYWORDS:

angiogenesis; antioxidant; apoptosis; breast; chemotherapy; free radicals; invasion; ionizing radiation; melatonin receptors; molecular mechanisms; prostate

PMID: 28420185 DOI: 10.3390/ijms18040843

25 Replies

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  • So much for a "paucity" - another paper has just been published. It too is a review paper. Unusual for a new paper - the full text is free. Here is the PCa section:

    "Prostate cancer

    "Prostate cancer is the second most frequently occurred cancer and the fifth leading cause of cancer mortality in men [91]. It was found that melatonin at pharmacological concentrations could inhibit cell growth of both androgen-dependent and androgen-independent prostate cancer [92], through various mechanisms.

    "In vitro studies

    "Melatonin significantly suppressed the expression of angiogenesis-related proteins HIF-1α, HIF-2α and VEGF at mRNA level of PC-3 cells under hypoxia, and upregulation of miRNA3195 and miRNA374b could mediate this anti-angiogenic property of melatonin [93]. Furthermore, melatonin presented anti-proliferative effects on prostate cancer cell lines, LNCaP and 22Rv1, and the mechanism might involve inactivation of NF-κB, via melatonin MT1 receptor-induced dual activation of (Gαs)/protein kinase A (PKA) and (Gαq)/protein kinase C (PKC), causing transcriptional upregulation of p27Kip1. The mechanism also involved downregulation of activated AR signaling via PKC stimulation [94, 95]. Another study documented that melatonin suppressed HIF-1α accumulation via inactivating sphingosine kinase 1 pathway and scavenging free radicals in hypoxic PC-3 cells, thus melatonin could act as a potent anti-cancer supplement for prostate cancer therapy [96]. Sirt1 (sirtuin 1) is a NAD+-dependent histone deacetylase and overexpressed in prostate cancer cells [97]. Melatonin significantly suppressed Sirt1 activity in vitro in multiple human prostate cancer cell lines, accompanied by a significant reduction in the proliferative potential of PCa cells [98]. In addition, melatonin could cause phenotypic changes, mainly neuroendocrine differentiation, thereby sensitizing human prostate cancer cells to apoptosis induced by cytokines, such as TNF-α or TRAIL [99]. Overexpression of Period 2 (Per2) gene could lead to a significant decrease of PCa cell growth and viability, and melatonin treatment could inhibit proliferation of prostate cancer cells by resynchronizing dysregulated circadian rhythm circuitry through upregulating Per2 and Clock genes and downregulating Bmal1 [100].

    "In vivo studies

    "Daytime blue light could increase nocturnal melatonin and then enhance the inhibition on human prostate cancer growth on male nude rats, as shown by decreased tumor growth rates, tumor cAMP levels, aerobic glycolysis (Warburg effect), uptake-metabolism of linoleic acid, and growth signaling activities [101]. In another study, melatonin in LNCaP human prostate cancer cells xenografted mice inhibited the xenograft growth rate by exerting an anti-angiogenesis effect by reducing xenograft microvessel density and expression of Ki67, and elevating expression of HIF-1α and phosphorylation of Akt. Melatonin also restored the redox imbalance by promoting expression of Nrf2 [102]. Furthermore, human volunteer nighttime-collected, melatonin-rich blood dampened signal transduction, metabolic and growth activity in tissue-isolated PC-3 cancer xenografts, via a melatonin MT1 receptor-mediated mechanism. On the contrary, blood collected from human subjects exposed to LAN exerted an exactly opposite effect via suppression of the nocturnal circadian melatonin signal [103]. Besides, oral administration of melatonin significantly inhibited prostate cancer tumorigenesis as characterized by reduction in prostate and genitourinary weight, serum IGF-1/IGFBP3 ratio, and mRNA and protein levels of PCNA and Ki-67, which were accompanied with a significant reduction in Sirt1 [98].

    "Collectively, these scientific literatures support the potential application of melatonin in the prevention and treatment of prostate cancer. Especially, melatonin could exert antiproliferative activity on androgen-independent prostate cancer cells (e.g. PC-3 cells), which makes melatonin a clinical choice to postpone the relapse of hormone-refractory or castration-resistant prostate cancer in combination with androgen deprivation therapy.?

    -Patrick

    ncbi.nlm.nih.gov/pubmed/284...

    Oncotarget. 2017 Mar 18. doi: 10.18632/oncotarget.16379. [Epub ahead of print]

    Melatonin for the prevention and treatment of cancer.

    Li Y1, Li S2, Zhou Y1, Meng X1, Zhang JJ1, Xu DP1, Li HB1,3.

    Author information

    1

    Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China.

    2

    School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

    3

    South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, Guangzhou, China.

    Abstract

    The epidemiological studies have indicated a possible oncostatic property of melatonin on different types of tumors. Besides, experimental studies have documented that melatonin could exert growth inhibition on some human tumor cells in vitro and in animal models. The underlying mechanisms include antioxidant activity, modulation of melatonin receptors MT1 and MT2, stimulation of apoptosis, regulation of pro-survival signaling and tumor metabolism, inhibition on angiogenesis, metastasis, and induction of epigenetic alteration. Melatonin could also be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. Melatonin could be an excellent candidate for the prevention and treatment of several cancers, such as breast cancer, prostate cancer, gastric cancer and colorectal cancer. This review summarized the anticancer efficacy of melatonin, based on the results of epidemiological,experimental and clinical studies, and special attention was paid to the mechanisms of action.

    KEYWORDS:

    anticancer; apoptosis; mechanisms of action; melatonin; receptor

    PMID: 28415828 DOI: 10.18632/oncotarget.16379

  • Certainly worrth trying. Have to research the dose though. Been taking only 3 to 5 mg. The side effects are positive, a good nites sleep and more.

  • High dose of at least 20 mg is suggested.

  • Thanks lulu

  • How are you taking 50 mg? I take about 5 per night. Are you taking 10 5 mg tabs?

    Nalakrats

  • It can be found in 20 mg dose. See Lef.org which Life Extension Foundation. I am away from my cabinet so cannot locate brand name. Also can be found as liquid. Studies in Italy, done a while ago, showed 20 mgs daily was a cancer-fighting dose. It can be difficult to start - can be a kind of hangover feeling. I had to try it 3x over a few year period before my 4th try turned out great. I use it still from time to time. 24 years out from original diagnosis. Founded Annie Appleseed Project to provide this kind of info.

  • I take 5 10 mg caps before bed.

    Note that it can make dreams seem more vivid for some, but I sleep like a baby for the first 4 hours.

    I get up at 5 am - no grogginess. Can't relate to those who say there is a residual effect. Receptors become insensitive to it as the night progresses.

    -Patrick

  • Grate results!

  • I take Vital nutrients melatonin 20 mg caps , 60 per bottle.. high quality..

  • Everyone of us should be using Melitonin..

  • OK, a daily dose of Melatonin it is. I had tried it as a sleep aid, but it quit working at low dosages. Intolerant? Well, I'm on it again. Thank you.

    Joe

  • Are you aware of studies with human prostate cancer patients, and if so, what dose levels were used?

    Thanks for all your work Patrick with your posts. I appreciate them and am sure that many others do as well.

  • Here's an old study that used 20 mg:

    ncbi.nlm.nih.gov/pubmed/907...

    "Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone."

    & another:

    ncbi.nlm.nih.gov/pubmed/891...

    "A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients."

    I would say that 20 mg is the lowest dose for cancer.

    LEF used to say 40 mg, but upped it to 50.

    -Patrick

  • I too have followed the evidence on Melatonin. Since it is not patentable, Big Pharma will never pay attention. They have specifically told me from various conference podiums: "Ann, we cannot patent that". End of conversation. But as Patients and Advocates, we clearly cannot let that happen. I tried taking melatonin 3 separate times (after reading studies and being inspired) but had that hangover feeling next day. Finally on my 4th try, it was fine. I still often take it for sleep. I am 24 years out from diagnosis and founder of Annie Appleseed Project (information, education and Advocacy around natural therapies for all cancers).

  • Be careful if you have RA like I do. "Melatonin may increase the strength of the immune system, which can cause problems for people with severe allergies, rheumatoid arthritis, lymphoma and other conditions linked to overactive immune systems, according to the American Cancer Society." I tried this and developed severe pain in my hands.

  • I've only been taking 3mg nightly. Going to have to bump that up.

  • Here's some more discussion on melatonin's cancer fighting qualities: canceractive.com/cancer-act...

    Strange, and grateful, to be only learning this now after using this in small doses every night for years.

  • You will benefit..

  • When do you take the melentonin? Found even at 10mg it keeps my dad awake.

  • Just before bed.

    As I mentioned, dreams can become more vivid, which disturbs sleep for some. Perhaps Relora would help those people. It's a non-narcotic calming supplement with anti-PCa properties.

    -Patrick

  • Before bed, at least 20 mg.

  • Asked my naturalpathic oncologist who prescribed it for me.He says 20 mg ,no more..I've done it nightly for 2yrs..good luck!

  • You are correct.Ive taken 20 mg. Each night for 2 yrs..My Nat. Dr. Told me it's great for cancer..Thank you for this info...I'll look into an increase if advised.Very interesting about its affect on mets..

  • Patrick,

    Been taking 10 mg of Melatonin for some time. Recently while reading elsewhere I came across a Memorial Sloan Kettering Cancer Center (MSKCC) web site that caution those that use it and that also are taking blood thinners because they have A-Fib. They state a Pub-Med article published 3/2008 in which it states that Melatonin is associated with lower plasma levels of factor VIII and fibrinogen. As such, the supplementation of Melatonin while also on anticoagulant meds may increase the risk of adverse effects. MSKCC also warns that because Melatonin alters estrogen levels, patients with hormone-sensitive cancers should consult physicians before considering melatonin. After reading through this thread that you initiated, I was contemplating boosting my dosage from 10 to 20 mg as suggested by some but now I am not sure considering that 1) I am on the anti-coagulant Eliquis and 2) I an currently treating Pca through the use of estradiol patches. Have any thoughts/suggestions?

    JAL

  • Joel,

    There were 2 papers of interest in 2008. In the one that MSKCC cited [1], healthy men were given 3 mg melatonin, resulting in:

    "lower mean levels of FVIII:C ... and of fibrinogen ... than those on placebo explaining 14 and 17% of the respective variance."

    "A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity."

    Men with PCa or other cancers tend to have altered coagulation factors & it might be beneficial to lower the risk of coagulation. I use a high dose of nattokinase, which lowers fibrinogen. When last measured it was in the lower part of the observed range. I think this a safer place to be than the high end. Unfortunately, I didn't check FVIII.

    LEF has their annual sale on blood tests at the moment:

    lifeextension.com/Vitamins-...

    lifeextension.com/Vitamins-...

    Of course, a test at 8 am might not reflect levels 6 hours earlier.

    The statement "There might be a dose-response relationship ..." is not useful. Why didn't they explore this with higher doses?

    Typically, responses to hormones are self-limiting.

    In any event, I wouldn't be concerned as long as tested numbers are in the normal range.

    In the other paper [2] - same team (same men?) - they were looking at the procoagulation response to stress:

    "Oral melatonin attenuated the stress-induced elevation in the sensitive coagulation activation marker D-dimer", but changes in "FVII:C, FVIII:C, fibrinogen ... did not significantly differ between groups."

    The danger of sn anticoagulant is that, in the event of a serious physical injury, one might bleed-out on the way to the ER. (With Warfarin, best to swallow some vitamin K ASAP. The other drugs are more problematic.) Melatonin before bed should be cleared by morning. Perhaps the effect on coagulation factors wears off quickly during the day? Trauma to the body has a profound effect on the factors, of course.

    Regarding estradiol [E2], while melatonin may offer protection in BCa, with an E2 patch for PCa, the benefits of melatonin might be blocked by the E2 (IMO).

    -Patrick

    [1] ncbi.nlm.nih.gov/pubmed/182...

    [2] ncbi.nlm.nih.gov/pubmed/184...