The rationale for treating uveal melanoma with adjuvant melatonin: a review of the literature

Anna Hagström, Ruba Kal Omar, Pete A Williams, Gustav Stålhammar, Anna Hagström, Ruba Kal Omar, Pete A Williams, Gustav Stålhammar

Abstract

Background: Uveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer.

Methods: Articles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review.

Results: Melatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma.

Conclusions: Given its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.

Keywords: Adjuvant treatment; Choroidal melanoma; Dormancy; Melatonin; Metastasis; Micrometastasis; Rationale; Survival, review; Uveal melanoma.

Conflict of interest statement

Gustav Stålhammar has received honoraria for consultancy and service on an advisory board (Santen SA). The other authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Literature search. The selection of articles for this analysis was performed in three steps. Articles were identified using specific search terms, abstracts were then screened, and lastly, full text articles were assessed for eligibility based on our exclusion criteria. Through this process 147 articles were selected and included in this review
Fig. 2
Fig. 2
Melatonin synthesis pathway. Tryptophan is hydroxylated by tryptophan hydroxylase (TPH) to 5-hydroxytryptophan which is subsequently decarboxylated by aromatic amino acid decarboxylase (AADC) resulting in serotonin. Serotonin is converted to N-acetylserotonin by Arylalkylamine N-acetyltransferase (AA-NAT) which is then catalyzed by N-acetylserotonin O-methyltransferase (ASMT) to produce melatonin
Fig. 3
Fig. 3
The anatomy of melatonin secretion. The production and release of melatonin are mainly mediated by postganglionic retinal nerve fibers that exits the eye through the optic nerve, pass through the retinohypothalamic tract to the suprachiasmatic nucleus and then to the pineal gland via the superior cervical ganglion. This axis is activated by darkness and suppressed by light. The circadian rhythm of melatonin secretion is to a lesser extent also controlled by the suprachiasmatic nucleus
Fig. 4
Fig. 4
Oncosuppressive mechanisms mediated by melatonin. Melatonin (MLT) activates the high-affinity G protein-coupled receptors MT1 and MT2 which reduce the transcriptional activity of NF-κB and activates phosphorylation cascades mediated by mitogen-activated protein kinases (MAPKs) including MEK1/2, ERK1/2, JNK, and p38. In turn, NF-κB inhibition and MAPKs activation inhibit cell growth and motility and promote apoptosis and DNA damage repair through accumulation of oncosuppressors such as p53, p27kip1, and p21. NF-κB inhibition and MAPKs activation also activates DNA repair complexes such as P53/PML/H2AX on DNA damage sites, and transcriptional control of genes involved in the cell cycle, apoptosis, and invasiveness. Further, melatonin can bind to the intracellular protein calmodulin (CaM) and reduce the Estrogen Receptor α (Erα) response in ER positive cells by impairing the formation of a proper E2–Erα–CaM complex on target genes. Melatonin downregulates the nuclear RZR receptors (RZR alpha, RZR beta, ROR alpha 1, RZR alpha 2, ROR alpha 3 and ROR gamma), inhibiting growth, angiogenesis and HIF-1α activity. Arrows indicate activation, while dashed blunt lines indicate inhibition. Activation indicates an increase in protein or activity levels, while inhibition indicates a decrease in protein or activity levels

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