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 just some of the anti-cancer properties of melatonin:

Angiogenesis: Melatonin can inhibit the process of angiogenesis, which is the formation of new blood vessels. This is crucial in cancer as tumors need blood vessels to supply them with nutrients for growth.
Apoptosis: Melatonin can induce apoptosis by selectively inducing excessive oxidative stress in cancer cells.
Autophagy: Melatonin can influence autophagy, a process where cells degrade and recycle their components. This can help to prevent the survival of cancer cells.
Endoplasmic reticulum stress: Melatonin can induce endoplasmic reticulum stress in cancer cells, which can lead to cell death.
Nutrient deprivation: Tumors appear to have the same sleep-wake cycle as the body. At night, when melatonin levels are at their highest, tumors are more dormant and exhibit decreased nutrient uptake. The higher melatonin levels seem to render tumors “less cancer-like” during nighttime hours. In contrast, during the day when melatonin levels drop, tumors exhibit active nutrient-seeking behavior, making them “more cancer-like.” Studies suggest that taking daytime melatonin may hinder tumor growth and spread by disrupting its nutrient absorption capabilities during the waking hours.
DNA methylation: Melatonin has been found to alter the status of DNA methylation in different cancer cells and models, such as malignant glioma and breast carcinoma.
Regulation of survival signaling: Melatonin has been shown to regulate survival signaling pathways in cancer cells.
Suppression of metastasis: Melatonin has been shown to suppress metastasis (the spread of cancer cells).
Regulation of epigenetic modifications: Melatonin has been shown to regulate epigenetic modifications that contribute to malignant transformation.
Cancer stem cells: Melatonin has been found to block the invasion and migration of cancer stem cells.
DNA Damage Response (DDR): Melatonin is shown to affect DDR, a signaling pathway that can ultimately control cell proliferation and apoptosis.
Inflammation: Melatonin reduces the secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-2), interleukin-6 (IL-6), and interferon-gamma (IFN-γ). These cytokines are often associated with inflammation and can contribute to the progression of cancer. In addition to reducing these pro-inflammatory cytokines, melatonin also enhances the amounts of anti-inflammatory cytokines such as IL-4, IL-10, and IL-27. These cytokines can help to control and reduce inflammation, which can be beneficial in slowing the progression of cancer.
Inverted pH gradient: Cancer cells often show an inverted pH gradient, with a more acidic extracellular environment and more alkaline intracellular pH compared to normal cells. This inversion supports cancer cells in various ways, including promoting tumor motility, invasion, and metastasis, and contributing to treatment resistance. Melatonin has been found to target this aberrant pH regulation and disrupt cancer’s ability to survive.
Immune regulation and tumor microenvironment interaction: Melatonin can potentiate cellular immunity by increasing the secretion of interleukin-2, interleukin-10, and interferon-γ, which in turn activate the T cells. Melatonin also contributes to tumor behavior by interacting with the tumor microenvironment, which has critical functions in suppressing or promoting carcinogenesis.
Chemosensitizing: Melatonin can enhance the effectiveness of chemotherapy drugs. It does this by increasing the sensitivity of cancer cells to these drugs, making them more susceptible to the treatment. This can lead to a greater reduction in tumor size and potentially improve patient outcomes.
Radiosensitizing: Melatonin can also increase the sensitivity of cancer cells to radiation therapy. This means that the cancer cells are more likely to be damaged by the radiation, leading to their death. This can enhance the effectiveness of radiation therapy in treating cancer.
Prion proteins: The cellular prion protein (PrP C), traditionally associated with neurodegenerative diseases, is increasingly being linked to cancer. Found in neurons and other peripheral organs, PrP C is overexpressed in various cancers like gastric, breast, and colon cancer, often indicating poor survival rates and chemotherapy resistance. Its overexpression is implicated in cancer proliferation, metastasis, and even cancer stem cell behavior, particularly in aggressive brain tumors like gliomas. The gene coding for prion proteins (PRNP) also interacts with the p53 gene, both of which are associated with cancer development and spread. Prions may further contribute to cancer by altering gene regulation and activating pathways like the mitogen-activated protein kinase (MAPK) that promote cancer growth. Recently, melatonin has been found to inhibit the cancer-promoting effects of prion proteins.
microRNAs (miRNAs) and long non-coding RNAs (lncRNAs): The roles of miRNAs and lncRNAs in cancer are complex and multifaceted. Both types of molecules are involved in the regulation of gene expression, and their dysregulation can contribute to tumorigenesis, metastasis, and resistance to therapy. Melatonin is thought to interact with and regulate the lncRNAs-miRNAs axis by affecting RNA alternative splicing events through its receptor MT1, potentially offering a new avenue for cancer treatment.
Reduction of side effects: In addition to enhancing the effectiveness of chemotherapy and radiation therapy, melatonin can also reduce some of the side effects associated with these treatments. For example, it has been shown to reduce the severity of mucositis (a common side effect of chemotherapy and radiation therapy involving inflammation and ulceration of the mucous membranes) and cardiotoxicity (damage to the heart muscle caused by chemotherapy drugs).

Comments: Due to its low bioavailability (around 3%), short half-life (40-60 minutes), and rapid elimination from circulation, for clinical utility and treatment efficacy, in my expert medical opinion, the total daily dosage needs to be 500-2000 mg and split into 6-12 daytime doses administered every 1-2 hours over a 12-hour period. After an adustment period of 1-3 weeks, surprisingly, high-dose melatonin causes little-to-no daytime sleepiness, and to help mitigate it further, a desktop light therapy lamp can be used (click here). To improve treatment efficacy, liposomal melatonin should be used for the following reasons:

Improved solubility: Many compounds (including melatonin) have poor water solubility, which can hinder absorption and bioavailability. Encapsulation within liposomes can improve the solubility of these compounds, leading to better absorption and distribution.
Increased circulation time: Liposomes can protect encapsulated compounds from rapid degradation or removal from the bloodstream. For instance, liposomes can prevent drug recognition by the mononuclear phagocyte system (MPS) or the reticuloendothelial system (RES), leading to prolonged circulation times. This can increase the half-life of the drug and maintain therapeutic levels for extended periods.
Controlled release: Liposomal formulations can control the release of the drug over time, offering a sustained-release profile. This can help maintain drug levels within a therapeutic window for extended periods, further enhancing the half-life.
Enhanced accumulation in tumor tissue: Due to the Enhanced Permeability and Retention (EPR) effect, nanoparticles like liposomes tend to accumulate in tumor tissues. This is because tumors often have leaky vasculature and impaired lymphatic drainage. This property can be exploited to enhance the delivery of anticancer drugs to tumor tissues.

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