Disclaimer:  This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on literature review at the time of the blog and may change as new evidence evolves.

Melatonin In Cancer Treatment

Can melatonin supplementation impact cancer development in a non-cancer patient? Can it affect cancer growth rates when added to standard therapies in cancer patients?



I. Historical Context

Figure 1: Melatonin (C13H16N2O2) is a pleiotropic, regulatory hormone involved in many biological processes. (Image courtesy of Memorial Sloan Kettering Cancer Center)
Figure 1: Melatonin (C13H16N2O2) is a pleiotropic, regulatory hormone involved in many biological processes. (Image courtesy of Memorial Sloan Kettering Cancer Center)

Melatonin, or 5-methoxy-N-acetyltryptamine, is a hormone synthesized primarily by the pineal gland. Since its discovery over sixty years ago, melatonin has been the subject of extensive preclinical and clinical research (1). Over the course of the 20th century, scientific investigators have uncovered many of melatonin’s physiological functions. One of its best characterized roles is as an influencer of human circadian rhythms; melatonin synthesis rises in darkness and falls in the presence of light (2). That said, disruption of this cyclic rhythm can have dire consequences extending far beyond degraded sleep-wake cycles. According to one line of evidence, such disruption may promote the development and progression of tumors (3).


II. Mechanisms of Action

In addition to maintaining human circadian rhythms, melatonin exerts a number of distinct effects that counteract cancer growth (4). Across multiple studies, researchers have shown that melatonin enhances the activity of natural killer cells, inhibits angiogenesis, suppresses tumor metabolism, and functions as a potent antioxidant (5)(6)(7)(8). Melatonin mediates these diverse activities by binding a pair of G-protein coupled receptors (MT1, MT2), which are expressed broadly throughout the central nervous system and peripheral tissues (9). Once bound, melatonin stimulates an immune response by promoting the production of interleukins and supporting cytotoxic T cell activation and proliferation.1 MT1 receptor activation also blocks the phosphorylation of calmodulin, cAMP-binding protein, and steroid receptor coactivator-1 (10). Because melatonin exerts pleiotropic effects through multiple, separate mechanisms of action, it may prove useful in the treatment of several kinds of cancers.


III. Results from Scientific Literature

Figure 2: Oral melatonin supplements vary in tablet size, quantity, and quality but usually are marketed to consumers seeking a sleep aid. (Image courtesy of Nature’s Bounty/Amazon)
Figure 2: Oral melatonin supplements vary in tablet size, quantity, and quality but usually are marketed to consumers seeking a sleep aid. (Image courtesy of Nature’s Bounty/Amazon)

Melatonin may have therapeutic value in patients with estrogen receptor (ER)-positive breast cancer. The growth of many mammary tumors depends, in part, on the presence of sex hormones known as estrogens (11). Synthesis of estrogens in the body is mediated by an enzyme called aromatase, which belongs to the cytochrome P450 family (12). Melatonin appears to reduce aromatase activity by downregulating upstream cyclooxygenase 2 (COX2) signaling pathways, including ERK1/2, JNK, p38 MAPK, and NF-NF-kB (13). This change leads to falling concentrations of the tumor promoter prostaglandin E2 and cyclic adenosine monophosphate (cAMP), which is a secondary messenger molecule key for signal transduction (14). In this context, reduced cAMP culminates in decreased activation of specific DNA sequences (promoters) corresponding to aromatase production. Thus, by blocking aromatase production, melatonin impedes estrogen synthesis and the associated risk of breast cancer (15).


Additional evidence suggests melatonin can complement the activity of other anticancer agents and mitigate the negative effects of radiotherapy. In one report, researchers noted that concomitant use of melatonin enhanced the anticancer activity of the chemotherapy docetaxel in MC7F human breast cancer cell lines. At the molecular level, melatonin appears to promote expression of pro-apoptotic genes (Bad, Bax) while inhibiting expression of Bcl2 – another gene whose protein product prevents cell death (16). Beyond this mechanism, melatonin also counteracts radiation-induced expression of TNF-α, which is a cytokine that increases aromatase activity and impedes differentiation of adipocytes. By acting on PPARy and C/EBP-α, melatonin counteracts harmful changes mediated by TNF-α (17). Despite these findings, melatonin when used alone does not result in cancer cell apoptosis.2 Current evidence indicates it has more potential as a natural, adjuvant therapy with a favorable tolerability profile.


IV. Cost and Availability

Oral formulations of melatonin are readily available for purchase in both immediate-release and controlled-release forms. Tablet size can vary significantly among manufacturers, although most often range between 1 mg to 10 mg. Relative to other treatments used for cancer, melatonin supplements are affordable; a bottle containing 240 tablets (3 mg each) retails for $7.74 or approximately $0.03 per 3 mg (18). In the United States, melatonin is regulated as a dietary supplement and receives less stringent regulation from the U.S. Food and Drug Administration (19). Although this ease of access is useful for individuals interested in incorporating the supplement into their diets, consumers must exercise caution if they seek to use melatonin regularly. Less oversight over the production of melatonin supplements may contribute to quality control issues among brands. Researchers testing 31 brands of supplements discovered that melatonin content varied from -83% to +478% of the labelled dose. Lot-to-lot variability within a particular brand differed by as much as 465%. Additionally, approximately one quarter (26%) of tested melatonin products also contained traces of serotonin (5-hydroxytryptamine) – a contaminant and controlled substance used to treat neurological disorders (20).


Another barrier to widespread melatonin adoption, beyond quality control issues, is a lack of standard protocols surrounding dosing. According to Ann Pressler, a nurse practitioner at the Cleveland Clinic, “individuals should take between 0.5 mg and 3 to address restlessness or insomnia.” Higher doses can increase daytime sleepiness, reduce focus, and cause feelings of chilliness (21). Even wider variability exists when assessing doses of melatonin used in patients with cancer. Multiple clinical trials investigating the clinical utility of melatonin as a cancer therapy examined it at a dose 20 mg/day hora somni (just before bed) for a period of two months (22). That said, others have evaluated melatonin at doses of 10 mg/day and 40 mg/day (23)(24). Since these trials concluded in the 1990s, no consensus has emerged regarding melatonin dosing in cancer patients.


V. Completed Clinical Trials

Within the last ten years, researchers have conducted a minimum of six clinical human studies evaluating the effects of melatonin in cancer patients (25).

Their findings are summarized in the following table:

Table 1: Published clinical human studies evaluating the efficacy of melatonin in patients with cancer between 2011 and 2021. Adapted from Talib et al., 2021.
Table 1: Published clinical human studies evaluating the efficacy of melatonin in patients with cancer between 2011 and 2021. Adapted from Talib et al., 2021.

AE = adverse events; CR = complete response; MDD = major depressive disorder; PR = partial response


In addition to the studies summarized in Table 1, researchers have experimented with high-dose melatonin regimens of up to 300 mg/day (26). Although this dose exceeds the quantity recommended by most clinicians, melatonin itself has a median lethal dose (LD50) of 3.2 g/kg in laboratory rats. Scaling this quantity up to the size of an average human adult, the LD50 of melatonin would be 224g (27). Because the physiological limit of melatonin is relatively high, toxicity never presents as a practical concern in studies; participants in one investigation took up to 1 g melatonin per day and experienced no observable side effects (28). What remains markedly more unclear is the precise value of such high-dose approaches, particularly in patients with cancer. It is important to note that proponents of high-dose melatonin like Dr. Frank Shallenberger, founder of the Nevada Center for Complementary Medicine, use the hormone in conjunction with insulin potentiated therapy because of its Glut receptor affinity. Consequently, because his strategy entails a combination of treatments, it may not be reproducible by people who seek to self-medicate with commercial melatonin supplements (29). His findings, while intriguing, appear anecdotal, and available, high-quality evidence corroborating melatonin’s ability to lessen the effects of radiotherapy and chemotherapy are still limited. That said, the positive conclusions drawn from the Wang et al. (2012) systematic review of existing randomized, controlled clinical trials help justify the funding of future, well-designed studies whose results can bring clarity to melatonin’s utility as an adjuvant therapy (30).


VI. Current Clinical Trials

Indeed, promising preclinical data collected over the last few decades continues to fuel interest in melatonin as an adjunctive cancer therapy. As of September 2021, there are currently 4 trials listed on the ClinicalTrials.gov database that feature melatonin as an intervention in varying cancer populations. The parameters of each investigation, along with its completion date, is noted in the following Table 2:

Table 2: Currently active or actively recruiting trials assessing the efficacy and safety of melatonin treatment in patients with cancer. Data collected from ClinicalTrials.gov.
Table 2: Currently active or actively recruiting trials assessing the efficacy and safety of melatonin treatment in patients with cancer. Data collected from ClinicalTrials.gov.

ECOG = Eastern Cooperative Oncology Group Performance Status; RT = radiotherapy

* Estimated enrollment for study; final sample size not yet determined


VII. Conclusion

Although melatonin is not yet endorsed by clinical guidelines, the hormone has high potential as an adjuvant therapy in cancer. Today, more randomized, controlled clinical trials are warranted to validate promising findings from preclinical studies (31). These data, collected over the last few decades, contain some actionable insights useful for people seeking to live healthier lives. Because tumor markers are in a high state of activity when melatonin levels are low, it may be important to maintain a certain level of melatonin in the body nightly to prevent and combat cancer (32). Low melatonin levels are also more common in older people, and declining production over time may explain the increased risk for breast cancer in older women (33). Another at-risk population are individuals with continued exposure to artificially-lit environments common in urban areas (34). If future research shows a causative relationship between light exposure and cancer, melatonin may enter the cancer treatment armamentarium as an indispensable therapy. Until then, people may be able to take a simple concrete step today towards fighting cancer by getting a good night’s rest.


Stay strong, keep smiling and be your own best doctor,

- Chuck

Charles J. Meakin MD, MHA, MS


Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.

 

1 Samec M, Liskova A, Koklesova L, et al. Metabolic anti-cancer effects of melatonin: clinically relevant prospects. Cancers. 2021;13(12):3018.

2 Kong X, Gao R, Wang Z, et al. Melatonin: a potential therapeutic option for breast cancer. Trends Endocrinol Metab. 2020;31(11):859-871.

3 Chuffa L, Seiva F, Cucielo MS, et al. Clock genes and the role of melatonin in cancer cells: an overview. Melatonin Res. 2019;2(2):133-157.

4 Gonzalez A, Alonso-Gonzalez C, Gonzalez-Gonzalez A, et al. Melatonin as an adjuvant to antiangiogenic cancer treatments. Cancers (Basel). 2021;13(13):3263.

5 Tan SS, Zhan W, Poon CJ, et al. Melatonin promotes survival of nonvascularized fat grafts and enhances the viability and migration of human adipose-derived stem cells via down-regulation of acute inflammatory cytokines. J Tissue Eng Regen Med. 2018;12(2):382-392.

6 Alvarez-Garcia V, Gonzalez A, Alonso-Gonzalez C, et al. Antiangiogenic effects of melatonin in endothelial cell cultures. Microvasc Res. 2013;87:25-33.

7 Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night. Endocrine. 2005;27:179-188.

8 Ashrafizadeh M, Najafi M, Kavyiani N, et al. Anti-inflammatory activity of melatonin: a focus on the role of NLRP3 inflammasome. Inflammation. 2021;44(4):1207-1222.

9 Su S-C, Hsieh M-J, Yang W-E, et al. Cancer metastasis: mechanisms of inhibition by melatonin. J Pineal Res. 2017;62(1).

10 Hill SM, Belancio VP, Dauchy RT, et al. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer. 2015;22(3):R183-R204.

11 Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol Neoplasia. 1998;3(1):49-61.

12 Chen SA, Besman MJ, Sparkes RS, et al. Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15. DNA. 1988;7(1):27-38.

13 Yao C, Liu X, Zhou Z, et al. Melatonin attenuates expression of cyclooxygenase-2 (COX-2) in activated microglia induced by lipopolysaccharide (LPS). J Toxicol Envrion Health A. 2019;

14 Amin N, Shafabakhsh R, Reiter RJ, et al. Melatonin is an appropriate candidate for breast cancer treatment: based on known molecular mechanisms. J Cell Biochem. 2019;120(8):12208-12215.

15 Jin Y, Choi YJ, Heo K, et al. Melatonin as an oncostatic molecule based on its anti-aromatase role in breast cancer. Int J Mol Sci. 2021;22(1):438.

16 Alonso-Gonzalez C, Menendez-Menendez J, Gonzalez-Gonzalez A, et al. Melatonin enhances the apoptotic effects and modulates the changes in gene expression induced by docetaxel in MCF-7 human breast cancer cells. Int J Oncol. 2018;52(2):560-570.

17 Gonzalez-Gonzalez A, Nieto EG, Gonzalez A, et al. Melatonin modulation of radiation and chemotherapeutics-induced changes on differentiation of breast fibroblasts. Int J Mol Sci. 2019;20(16):3935.

18 Amazon.com. Nature’s Bounty Melatonin by, 100% Drug Free Sleep Aid, Dietary Supplement 3mg, - 3 mg 240 count. Accessed September 15, 2021.

19 National Center for Complementary and Integrative Health. Melatonin: what you need to know. https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know. Updated January 2021. Accessed September 15, 2021.

20 Erland LAE, Saxena PK. Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content. J Clin Sleep Med. 2017;13(2):275-281.

21 Pressler A. Melatonin: how much should I take for a good night’s rest? The short answer from a nurse practitioner. Cleveland Clinic. https://health.clevelandclinic.org/melatonin-how-much-should-i-take-for-a-good-nights-rest/. Published March 5, 2019. Accessed September 15, 2021.

22 Wang Y, Wang P, Zheng X, et al. Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis. Onco Targets Ther. 2018;11:7895-7908.

23 Lissoni P, Meregalli S, Fossati V, et al. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori. 1994;80(6):464-467.

24 Barni S, Lissoni P, Cazzaniga M, et al. A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates. Oncology. 1995;52:243-245.

25 Talib WH, Alsayed AR, Abuawad A, et al. Melatonin in cancer treatment: current knowledge and future opportunities. Molecules. 2021;26(9):2506.

26 Ma Z, Yang Y, Fan C, et al. Melatonin as a potential anticarcinogen for non-small-cell lung cancer. Oncotarget. 2016;7(29):46768-46784.

27 American Sleep Association. Melatonin: dosage, reviews & safety. https://www.sleepassociation.org/sleep-treatments/melatonin/. Updated 2021. Accessed October 7, 2021.

28 Nordlund JJ, Lerner AB. The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab. 1997;45:768-774.

29 Shallenberger, Frank IVC Conference Presentation 2018, Optimizing Oxidation in the Care of Chronically Ill Patients - YouTube

30 Wang Y, Jin B-z, Ai F, et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012;69(5):1213-1220.

31 Martinez-Campa C, Menendez-Menendez J, Alonso-Gonzalez C, et al. What is known about melatonin chemotherapy and altered gene expression in breast cancer. Oncol Lett. 2017;13(4):2003-2014.

32 Blask DE, Dauchy RT, Dauchy EM, et al. Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling, and tumor growth prevention. PLoS ONE. 2014;9:e102776.

33 Reiter RJ, Rosales-Corral SA, Tan D-X, et al. Melatonin, a full service anti-cancer agent: inhibition of initiation, progression, and metastasis. Int J Mol Sci.

34 Keshet-Sitton A, Or-Chen KI, Yitzhak S, et al. Can avoiding light at night reduce the risk of breast cancer? Integr Cancer Ther. 2016;15:145-152.