From Sleep Aid to Cancer Fighter: The Expanding Therapeutic Role of Melatonin

Melatonin, a powerful neurohormone secreted by the pineal gland and other organs, is a versatile substance involved in various cellular and molecular functions. Despite being identified over 50 years ago as a non-toxic substance that can suppress cancer, melatonin’s anti-cancer capabilities have yet to be fully taken advantage of by the medical profession. Due to the abundance of published data, however, many scientists believe that melatonin will eventually emerge as a frequently used therapeutic medication. Here are the known anti-cancer properties of melatonin:

Cell Death and Growth Inhibition

Apoptosis: Melatonin can induce apoptosis by selectively inducing excessive oxidative stress in cancer cells.
Cell cycle regulation: Melatonin slows cell cycle progression in a dose-controlled fashion, preventing cancer cell proliferation.
Autophagy: Melatonin can influence autophagy, a process where cells degrade and recycle their components.
Endoplasmic reticulum stress: Melatonin can induce endoplasmic reticulum stress in cancer cells, leading to cell death.
DNA Damage Response (DDR): Melatonin is shown to affect DDR, a signaling pathway that can ultimately control cell proliferation and apoptosis.

Metabolic Reprogramming

Nutrient deprivation: Tumors have the same sleep-wake cycle as the body. Melatonin renders tumors “less cancer-like” during nighttime hours, decreasing nutrient uptake.
Warburg effect reversal: Melatonin can reverse the Warburg effect in cancer cells, interfering with their altered metabolism.
Metabolism disruption: Melatonin restricts the pentose phosphate pathway, glycolysis, and the Krebs cycle, primarily lowering glucose uptake.
Inverted pH gradient: Melatonin targets the aberrant pH regulation in cancer cells, disrupting their survival ability.

Genetic and Epigenetic Regulation

DNA methylation: Melatonin alters the status of DNA methylation in different cancer cells and models.
Regulation of epigenetic modifications: Melatonin regulates epigenetic changes contributing to malignant transformation.
Telomerase suppression: Melatonin exerts a telomerase-suppressing response, inhibiting cancer cell immortality.
microRNAs (miRNAs) and long non-coding RNAs (lncRNAs): Melatonin interacts with and regulates the lncRNAs-miRNAs axis.

Signaling Pathway Modulation

Regulation of survival signaling: Melatonin regulates survival signaling pathways in cancer cells.
NF-κB signaling inhibition: Melatonin prevents NF-κB signaling excitation via MT1 receptor-mediated pathways.
Modulation of calcium signaling: Melatonin reduces Ca+2 influx mediated by steroids and inhibits MT1 receptor activation.
Hormonal pathway modulation: Melatonin has antiestrogenic effects in hormone-dependent cancers and can reduce estrogen receptor expression.

Tumor Microenvironment and Metastasis

Angiogenesis: Melatonin can inhibit the process of angiogenesis, which is the formation of new blood vessels.
Suppression of metastasis: Melatonin has been shown to suppress metastasis (the spread of cancer cells).
Inflammation: Melatonin reduces pro-inflammatory cytokines and enhances anti-inflammatory cytokines.
Immune regulation and tumor microenvironment interaction: Melatonin potentiates cellular immunity and interacts with the tumor microenvironment.
Cancer stem cells: Melatonin has been found to block the invasion and migration of cancer stem cells.

Oxidative Stress Regulation

Dual oxidative effects: At high pharmacological (i.e., high) doses, melatonin acts as a pro-oxidant, inducing cytotoxic effects specifically in cancer cells, while at physiological levels it typically functions as an antioxidant. This dose-dependent dual nature allows melatonin to selectively trigger oxidative damage in malignant cells while protecting normal cells.

Therapeutic Enhancement

Chemosensitizing: Melatonin can enhance the effectiveness of chemotherapy drugs.
Radiosensitizing: Melatonin can increase the sensitivity of cancer cells to radiation therapy.
Reduction of side effects: Melatonin can reduce side effects associated with chemotherapy and radiation therapy.

Protein Interactions

Prion proteins: Melatonin has been found to inhibit the cancer-promoting effects of prion proteins.

Extremely Low Oral Bioavailability

The pharmacokinetic data is quite striking – oral melatonin has a bioavailability of only about 2.5-3%, meaning 97% of what you take orally never reaches systemic circulation. This explains why standard over-the-counter doses (1-5mg) may be sufficient for sleep but inadequate for therapeutic anticancer effects. This poor bioavailability results from extensive first-pass metabolism in the liver, as confirmed in both the Andersen et al. pharmacokinetics study and the Schrire et al. systematic review.

Pharmacologic Dosing Requirements

For potential anticancer applications, substantially higher doses appear necessary. The preliminary study by Lissoni et al. utilized 1000mg (1 gram) daily in advanced cancer patients who had failed conventional therapies, achieving disease control in 54% of cases. This represents a 100-200× increase over typical sleep-aid dosing.

Current evidence suggests that to achieve therapeutic plasma concentrations, total daily dosages between 500 and 2000mg may be required, ideally divided into multiple doses throughout the day to maintain more consistent blood levels. This compensates for melatonin’s relatively short half-life (approximately 40-54 minutes) and poor oral absorption.

Safety Profile of High-Dose Melatonin

Perhaps most remarkably, high-dose melatonin appears surprisingly well-tolerated. The systematic review by Schrire and colleagues examined numerous studies using doses ≥10mg and found no significant increase in serious adverse events compared to placebo. Some studies have utilized extremely high doses—up to 3 grams daily—without reporting major toxicity concerns.

The most common side effects were mild and included drowsiness, headache, and dizziness. Interestingly, the Lissoni study using 1000mg daily reported good tolerability even in patients with advanced cancer and poor performance status.

References:

Akbarzadeh M, Movassaghpour AA, Ghanbari H, Kheirandish M, Fathi Maroufi N, Rahbarghazi R, Nouri M, Samadi N. The potential therapeutic effect of melatonin on human ovarian cancer by inhibition of invasion and migration of cancer stem cells. Sci Rep. 2017 Dec 6;7(1):17062.

Andersen LP, Werner MU, Rosenkilde MM, Harpsøe NG, Fuglsang H, Rosenberg J, Gögenur I. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacol Toxicol. 2016 Feb 19;17:8.

Bai L, Sun S, Su W, Chen C, Lv Y, Zhang J, Zhao J, Li M, Qi Y, Zhang W, Wang Y. Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO. Front Pharmacol. 2022 Sep 26;13:1007006.

Basirat U, Bin Tariq U, Moeen N, Jawhar ZH, Shoja SJ, Kareem AK, Ramírez-Coronel AA, Romero-Parra RM, Zabibah RS, Gupta J, Mustafa YF, Farhood B. A Systematic Review of the Chemo/Radioprotective Effects of Melatonin against Ototoxic Adverse Effects Induced by Chemotherapy and Radiotherapy. Curr Pharm Des. 2023 Jun 6;29(15):1218-1229.

Davoodvandi A, Nikfar B, Reiter RJ, Asemi Z. Melatonin and cancer suppression: insights into its effects on DNA methylation. Cell Mol Biol Lett. 2022 Sep 5;27(1):73.

Farhood B, Goradel NH, Mortezaee K, Khanlarkhani N, Salehi E, Nashtaei MS, Mirtavoos-Mahyari H, Motevaseli E, Shabeeb D, Musa AE, Najafi M. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization. Clin Transl Oncol. 2019 Mar;21(3):268-279.

Fernandez-Gil BI, Otamendi-Lopez A, Bechtle A, Vazquez-Ramos CA, Qosja N, Suarez-Meade P, Sarabia-Estrada R, Jentoft ME, Guerrero-Cázares H, Escames G, Schiapparelli P, Quiñones-Hinojosa A. Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma. Cells. 2022 Nov 2;11(21):3467.

Florido J, Rodriguez-Santana C, Martinez-Ruiz L, López-Rodríguez A, Acuña-Castroviejo D, Rusanova I, Escames G. Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells. Antioxidants (Basel). 2022 Aug 20;11(8):1621.

Gurunathan S, Qasim M, Kang MH, Kim JH. Role and Therapeutic Potential of Melatonin in Various Type of Cancers. Onco Targets Ther. 2021 Mar 18;14:2019-2052.

Hill SM, Frasch T, Xiang S, Yuan L, Duplessis T, Mao L. Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther. 2009 Dec;8(4):337-46.

Huang ZA, Huang YA, You ZH, Zhu Z, Sun Y. Novel link prediction for large-scale miRNA-lncRNA interaction network in a bipartite graph. BMC Med Genomics. 2018 Dec 31;11(Suppl 6):113.