What effects does melatonin have in cancer?

Greg:

Good question!

I will below summarize, from a recent internal review, the fundamental mechanisms that underlie the known positive benefits melatonin exerts in the cancer context, restricting my attention to causal pathways and activities, not to the human clinical outcomes these separately and often collectively influence, another story altogether although I hasten to note that all mechanisms discussed here have been evidenced in human clinical trials.

MELATONIN: A TOUR OF CORE ANTICANCER MECHANISMS

Antiproliferative Activity:

Melatonin exhibits direct antiproliferative activity [1,2,3,4], most likely consequent to its ability to inhibit, via activation of the high-affinity MT1 and low-affinity melatonin receptors (MT2, MT3) receptors, lineoleic acid uptake which appears to be the mechanism for its antiproliferative effects, given that 15-lipoxygenase is known to oxidize linoleic acid to 13-HODE (13-Hydroxy octadecadienoic acid) that provides an energy source for both tumor signaling molecules and tumor growth and is a known mitogenetic metabolite [5, 6].

Antioxidation:

Melatonin exerts dose-dependent antioxidative effect acting as a free radical scavenger [7,8.9.10,11,12,13], primarily via three of its metabolites, 3-OHM, AFMK, and AMK, two of which (AFMK and AMK) exert strong anti-inflammatory and immunoregulatory activities [14,15], with melatonin itself stimulating antioxidant enzymes [16], allowing it to be both radioprotective against cellular damage from the oxidative stress associated with ionizing radiation [17], as well as radiosensitizing - via p53-mediation with melatonin increasing the tumor suppressor gene/protein [18], such p53 modulation being an independent anticancer mechanism exerted by melatonin - by its regulation of proteins implicated in estrogen synthesis [19], although I hasten to note that recent in vitro data suggests that melatonin also exhibits conditional, context-specific pro-oxidant activity which appears to be mediated by its low-affinity binding protein calmodulin [20], being both concentration dependent as well as cell type dependent.

Pro-apoptotic Activity:

Melatonin causes the activation of the intrinsic and/or extrinsic cancer cell apoptotic pathways, via increasing the p53/MDM2p ratio (see above re melatonin's antioxidative activity) and downregulating the tumor-promotion associated with Sirt1 [21].

Cell Differentiation Induction:

Melatonin induces cell differentiation via control and regulation of the survival and differentiation of mesenchymal stem cells (MSCs), likely via the Wnt/β-catenin pathway, the MAPK pathway and TGF-β signaling [22,23].

Antimetastatic Activity:

Melatonin was found to lower tumor cell invasive potential via the up-regulation of the expression of adhesion proteins β-integrin and E-cadherin [24], and through antimetastatic effects on the epithelial–mesenchymal transition, based in part on the observation that plasma levels of melatonin were found to be significantly lower in patients with metastatic cancer than non-metastasized cancer patients [25], and this appears in part be secondary to the fact that melatonin inactivates MMP-2 and MMP-9 via down-regulation of the p38/MAPK pathway [26,27]; and by modulation of the expression of Rho-associated kinase protein-1 (ROCK-1) whose increased expression is known to promote tumor growth and metastasis [28].

Anti-angiogenic Activity:

This is via down-regulation of VEGF expression [29,30,31,32,33], thereby inhibiting cell proliferation, invasion, migration and tube formation, while also disintegrating any preformed capillary networks [34].

Antiestrogenic and Antiaromatase activity:

These endocrine pathways effects are via aromatase inhibition [35] - much like letrozole (Femara) and other aromatase inhibitors (AIs) - and via the downregulation of aromatase expression at the transcriptional level [36], in major part through the modulation of local estrogen biosynthesis [37] and through the act of melatonin binding to the MT1 receptor that has been demonstrated to be present in MCF-7 breast cancer cells [38], and also and independently serving as a natural SERM (selective estrogen enzyme modulator) much like like tamoxifen [39,40], with a clear and well-documented interaction of melatonin with estrogen-responsive pathways allowing it to behave as a natural antiestrogenic hormone [41,42], downregulating ER expression and blocking ER activation from DNA binding [43].

Immunomodulatory Activity (Immune response modulation):

This is a distinct immunoenhancive effect via promoting T‐helper cell response by the release of interleukin‐2,interleukin‐10 and interferon‐γ, while stimulating NK cell activity [44,45,46,47]. Melatonin's immunomodulatory effects also extend to direct induction of natural killer cell activity, immunosurveillance while also stimulation cytokine production (interleukin 2,6, 12; interferon gamma) [48,49].

Telomerase Reductive Activity:

Melatonin also exerts anticancer benefit through reduction of telomerase activity, which is activated in a wide variety of human cancers [50], with a dose-dependent decrease in the catalytic subunit of telomerase, TERT (Telomerase reverse transcriptase) [51].

Gene Expression Modulation:

Independent of antiestrogenic and antiaromatase activity, melatonin via activation of its MT-1 receptor, is known to inhibit the expression of key pro-cancer AKT, ERK1/2, PKA, PKC, c-SRC, GSK3β kinases and of RORα, RAR, RXR, VDR, PPARγ, Ap-1, Elk-1, CREB, NF-kB, and STAT3 transcription factors [52], and it know appears further that some aspects of melatonin's gene regulatory activity may be consequent to epigenetic phenomena [53].

Circadian Modulatory Effects:

Through reversal of Light at Night-induced circadian disruption, given the now well-established and intimate relationship across light at night (LAN) exposure, sleep duration, endogenous melatonin levels, and elevated breast cancer risk, with melatonin acting as both a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor (CRKI) [54] [55] [56] [57], with clear influence of the Light at Night as implicated in the development, promotion, and progression of breast cancer [58], and with and through effects on metabolic signalling pathways [59] [60], this association now reflected in IARC (International Agency for Research on Cancer)/WHO's classification of Light at Night as class 2a probable carcinogen [61].

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METHODOLOGY OF THIS REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), and the SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.

Constantine Kaniklidis

Research Director, No Surrender Breast Cancer Foundation (NSBCF)

Reviewer, Current Oncology

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