Cancers are the second leading cause of death worldwide, after cardiovascular diseases.
Cancers are a collection of diseases in which abnormal cells can divide uncontrollably and spread to nearby tissue. Cancers can arise in many parts of the body, which leads to a range of cancer types and can in some cases spread to other parts of the body through the blood and lymph systems.
Presently, various treatment strategies have been used as conventional treatments for patients with cancer, such as surgical removal of tissue, chemotherapy, radiotherapy, and immunotherapy. Advanced stages of cancer have relatively unfavorable clinical outcomes due to factors such as toxicity, chemoresistance, and other detrimental side effects.
The past number of years there has been increased evidence from experimental and clinical studies suggesting that melatonin exhibits a promising range of beneficial effects against cancer.
What is melatonin?
Melatonin is a natural hormone that, amongst other physiological functions, plays crucial roles as an antioxidant and in regulating the body’s circadian rhythm, also known as the biological clock, in the 24-hour sleep-wake cycle. Melatonin also regulates a seasonal rhythm, with higher levels of melatonin in the autumn and winter when nights are longer, and lower levels in spring and autumn when nights are shorter.
Sources of melatonin:
At least four different sources of melatonin contribute to the melatonin pool in humans. These are:
- Visible-light regulated melatonin originating from the tiny pineal gland in the brain at night, circulating in the cerebrospinal fluid and the bloodstream.
- The non-visible near infrared radiation (NIR) portion of sunlight regulated melatonin, which is produced during the day. NIR is the largest stimulus in the production of melatonin in the mitochondria of cells in the body (95%). This subcellular melatonin production (extra pineal) does not fluctuate with circadian rhythm, nor is it released into the circulation.
- The microbiome, consisting of, for example, the microbiota microorganisms in the gut, the skin, the respiratory tract, and even the vagina, is deemed to also make melatonin.
- As melatonin is present in plants and animals, the body also obtains melatonin from dietary sources.
- Melatonin can also be obtained from supplements.
Biological effects of melatonin:
Melatonin has a wide range of biological effects in the body, as there are melatonin receptors on the membranes of almost all cell types, allowing melatonin to bind.
Circadian rhythm: The best-known biological effect of melatonin is regulating the circadian rhythms, better known as the sleep-wake cycle. Nighttime production of melatonin results from the detection of light and dark by the retina of the eye, with the production of melatonin inhibited during the light of day and stimulated in the dark of night. When activated at night, the pineal gland secretes melatonin into the bloodstream as well as into the cerebrospinal fluid around the brain and spinal cord, from where it is carried to all areas of the body. Receptors in the cells and tissue of the body detect the peak in melatonin being circulated at night and signals to the body that it is time to sleep. Melatonin not only regulates the daily circadian rhythm, but also a seasonal rhythm, with higher levels of melatonin in the autumn and winter when nights are longer, and lower levels in spring and autumn when nights are shorter.
Antioxidant: Melatonin is known as a multifunctional antioxidant as it acts as a potent scavenger of harmful free radicals (molecules that are usually unstable and highly reactive, which may cause damage, especially in high concentrations, to biological molecules) and plays a role in neutralizing reactive oxygen species (ROS) (a type of unstable oxygen-containing molecule that easily reacts with other molecules in a cell and a build-up of ROS may cause damage to DNA). Free radical damage to DNA in cells may lead to cancer. The antioxidant effects of melatonin help to protect the mitochondria (which generates energy currency inside the cells in the body), as melatonin – working synergistically with vitamin D to optimize mitochondrial function – can protect it from oxidative damage.
Immunoregulating properties: Melatonin plays a role as an effector that can modulate the immune system. It may act as an immunostimulant under immunosuppressed conditions, contributing to a pre-activated state for a more effective early immune response, while also acting as an anti-inflammatory compound in the presence of severe immunity responses, such as acute inflammation.
Anti-inflammatory effects: Melatonin has been shown to possess anti-inflammatory effects by reducing tissue destruction during inflammatory reactions, such as reducing macromolecular damage in all organs through its ability to directly scavenge free radicals. Several studies have shown that melatonin plays a role in reducing chronic and acute inflammation.
Melatonin’s anti-cancer effects:
An increasing number of studies have indicated that melatonin has anticancer effects. Although the exact underlying mechanisms behind its anticancer effects remain unclear, the potential usage of melatonin for cancer treatment has come to the attention of scientists over the past number of years.
Studies have identified the regulatory effects of melatonin on tumor management in different stages of cancer by targeting various signaling pathways, including:
- tumor initiation – by inhibiting healthy cells from becoming malignant,
- tumor promotion – by reducing the downregulation of tumor suppression genes, and
- tumor progression – by inhibiting cancer cell growth.
Clinical studies have used melatonin, with promising results, in combination with other anticancer treatments:
- Chemotherapy – melatonin is used as an adjuvant (adjuvant therapy refers to additional cancer treatment to lower the risk of the cancer coming back).
- Radiotherapy – melatonin shows antitumoral outcomes and relieves drug resistance. (The use of melatonin to enhance the effect of radiotherapy has however so far been poorly studied in humans.)
- Immunotherapy – melatonin is used as adjuvant with other immunotherapy drugs.
- Cancer vaccine – melatonin has the potential to stimulate the immune system and may have a synergistic effect when combined with cancer vaccination. Cancer vaccines either treat an existing cancer or impede cancer development. Cancer cells arise routinely, and a tumor can develop if these cells are not destroyed by the immune system.
There are currently a few uncertainties with the use of melatonin as an anticancer drug:
- Chemical properties – the half-life (the time it takes the concentration to reduce to half the starting dose) of melatonin is short at approximately 45 minutes and the oral bioavailability (the extent of the substance that finally reaches the intended biological destination) is low.
- Measurement – how to precisely measure the melatonin concentration remains a challenge. Melatonin is found in blood plasma, in saliva, and in urine. Sample collection time is another important factor, as it is essential to collect multiple samples at different time points. It is also essential to select an appropriate assay kit to test melatonin levels, as numerous assay testing kits have been developed. Conflicting results in various studies point to a lack of standardization in factors such as which sample to collect, sample collection time, and the selection of assay kits, which hinders the determination of the exact therapeutic level of melatonin in cancer treatment.
- Dosing – although melatonin is acknowledged to have no significant toxicity or adverse side effects, research is yet to determine the optimal dosage of melatonin for cancer prevention or for adjuvant cancer therapy. The dosage in studies ranged from 0,3 mg to 1600 mg daily.
- Single or adjuvant anticancer drug – although several studies have shown the anticancer effect of melatonin, some studies have indicated that the use of melatonin alone exerted less or no effect on reducing cancer markers. Current evidence suggests that melatonin may be used as an adjuvant or protective anticancer drug to increase treatment efficacy and reduce adverse side effects. Most existing studies, however, used a relative low dosage of melatonin.
Known anticancer mechanisms of melatonin:
Several studies have reported that melatonin has various beneficial anticancer activities. In a nutshell, the most important of these intricate biochemical anticancer activities are the following:
- Apoptosis induction – normal programmed cell death (apoptosis) may be blocked in cancer cells and melatonin has been found to stimulate apoptosis in cancer cells.
- Cell proliferation inhibition – cancer cells are recognized by their ability to over-proliferate (multiply rapidly) and melatonin has shown antiproliferation effects in cancer cells.
- Effect on metastases – melatonin exhibits various mechanisms to restrain the spreading of cancer cells (metastases) to other regions in the body, for example by modulating cell-cell interaction.
- Genomic integrity of cells – genomic instability is one of the factors that leads to tumor growth in cancer cells and melatonin’s antioxidant activity plays an important role in protecting DNA from oxidative damage.
- Promoting cell apoptosis – ascancer cells lose control over apoptosis (programmed cell death), leading to uninhibited growth, melatonin has been shown to stimulate programmed cell death in cancer cells.
- Angiogenesis processes – angiogenesis refers to the formation of new blood vessels, which aids the growth of cancer cells. Melatonin has been shown to modulate tumor angiogenesis.
- Tumor-associated immune invasion – cancer cells can evade the immune response through various mechanisms, for example by immune suppression, while melatonin enhances the viability of immune cells.
- Tumor-promoting inflammation – there are a strong relationship between chronic inflammation and tumor development. Melatonin is known for its anti-inflammatory effects, which may have antitumor effects.
- Tumor dysregulated metabolism – cancer cells tend to convert most of the glucose in the bloodstream to lactate, which stimulates angiogenesis. Melatonin was shown to reduce glucose metabolism in cancer cells.
Conclusions:
The anticancer effects of melatonin in the treatment and prevention of various types of cancer have been widely studied in vitro in laboratories, in animal studies, as well as in some human studies. Combining melatonin with conventional anticancer therapies (such as chemotherapy) to reinforce their therapeutic effects, has shown encouraging results.
As there are ample data to implicate melatonin in promoting tumor suppression and slowing down the rate of tumor growth, it is of great interest in tumor therapy. The very low toxicity of melatonin, ready availability, and low cost make it a promising candidate for use in cancer prevention and treatment.
Despite the promising effects of melatonin in the treatment of cancer, there is still an insufficiency of reliable information in this regard. Findings from clinical studies are inconsistent due to varied dosages and times of administration.
Clinical trials are expensive, and there may also be a lack of a commercial incentive to develop a non-proprietary agent such melatonin, which is readily available and not manufactured under a trade name or protected by trademark or patent. Well conducted clinical trials are needed to better explore the anticancer mechanisms of melatonin in various types of cancer, as well as determining the safety profile, optimum dosage, and sample collection time, required for precise treatment.
References:
Use of melatonin in cancer treatment: Where are we? Published 29 March 2022. International Journal of Molecular Sciences. MDPI. (Publisher of Open Access Journals.) (www.mdpi.com)
Melatonin in cancer treatment: Current knowledge and future opportunities. Published 25 April 2021 in the journal Molecules. PubMed Central. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. USA. (www.ncbi.nlm.nih.gov)
Melatonin and cancer suppression: Insights into its effects on DNA methylation. Published 5 September 2022. Cellular & Molecular Biology Letters. BioMed Central Ltd. (www.cmbl.biomedcentral.com)
Mechanisms underlying tumor suppressive properties of melatonin. Published 27 July 2018. International Journal of Molecular Sciences. MDPI. (Publisher of Open Access Journals.) (www.mdpi.com)
Role and therapeutic potential of melatonin in various types of cancers. Published 18 March 2021. Dove Press. (Open access to scientific and medical research.) (www.dovepress.com)
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