Melatonin and Cancer
Melatonin is a hormone that is primarily produced by the pineal gland, a small endocrine gland located near the center of the brain, between the two hemispheres. The pineal gland is about the size of a pea and is responsible for the synthesis of melatonin from the amino acid tryptophan, which is converted to serotonin and then to melatonin through a series of enzymatic reactions. The rate-limiting enzyme in melatonin synthesis is arylalkylamine N-acetyltransferase (AANAT), which is primarily expressed in the pineal gland.
The production of melatonin follows a circadian pattern, with levels typically rising in the evening, peaking during the night (between 2 am and 4 am), and then decreasing towards morning. This circadian regulation is influenced by light exposure, particularly blue light, which suppresses melatonin production. The pineal gland receives input from the suprachiasmatic nucleus (SCN) of the hypothalamus, which is considered the master clock of the body's circadian rhythm. The SCN receives information about light exposure from the retina via the retinohypothalamic tract and relays this information to the pineal gland through a multi-synaptic pathway.
Melatonin production decreases with age, which may contribute to sleep disturbances and other age-related health issues. In children, melatonin levels are highest, and they gradually decline throughout adulthood. Besides light exposure and age, other factors can influence melatonin production, including stress, certain medications, and shift work that disrupts the normal sleep-wake cycle.
The amount of melatonin produced by the pineal gland varies throughout the day and night, following a circadian rhythm. The total amount of melatonin produced per day or week can vary depending on factors such as age, light exposure, and individual differences. In adults, the pineal gland typically produces around 5 to 25 micrograms (mcg) of melatonin per night, with an average of about 10 to 15 mcg. The peak production occurs between 2 am and 4 am, and the lowest levels are observed during the day. The total amount of melatonin produced per day is estimated to be around 30 to 50 mcg.
While the pineal gland is the primary source of melatonin, small amounts of this hormone are also produced in other tissues, such as the retina, gastrointestinal tract, and skin. However, the physiological significance of extra-pineal melatonin production is not yet fully understood.
Melatonin plays a crucial role in regulating the sleep-wake cycle and has been linked to various other physiological processes, such as immune function, antioxidant defense, and regulation of blood pressure. Due to its wide-ranging effects, melatonin has been studied for its potential therapeutic applications in sleep disorders, jet lag, cancer, and neurodegenerative diseases.
Melatonin’s Anti-cancer Properties
Melatonin has been investigated for its potential anticancer properties. Numerous in vitro and in vivo studies have demonstrated that melatonin may play a role in regulating the cell cycle, inducing apoptosis (programmed cell death) in cancer cells, and inhibiting angiogenesis (blood vessel formation) in tumors. These properties suggest that melatonin could potentially be used as an adjuvant therapy in cancer treatment.
One of the mechanisms by which melatonin may exert its anticancer effects is through its ability to regulate the cell cycle. By controlling the progression of cells through the various phases of the cell cycle, melatonin may help prevent the uncontrolled growth and division of cancer cells. Additionally, melatonin has been shown to induce apoptosis in cancer cells, which is a critical process in preventing the spread and growth of tumors.
Another important aspect of melatonin's anticancer potential is its ability to inhibit angiogenesis. Angiogenesis is the formation of new blood vessels, which is essential for the growth and metastasis of tumors. By inhibiting this process, melatonin may help limit the blood supply to tumors, thus reducing their growth and spread.
Furthermore, melatonin has exhibited antioxidant and immunomodulatory properties, which may contribute to its anticancer potential. As an antioxidant, melatonin can help protect cells from oxidative stress and damage caused by reactive oxygen species (ROS). This is important because oxidative stress has been linked to the development and progression of various types of cancer. Moreover, melatonin's immunomodulatory effects may help enhance the body's natural immune response against cancer cells, potentially improving the efficacy of cancer treatments.
Melatonin’s Effect on Chemotherapy
Several studies have investigated the potential of melatonin to enhance the efficacy of chemotherapeutic agents and reduce the associated side effects. Here are some examples of what has been found in the research:
Cisplatin:
In a study by Lissoni et al. (1996), patients with advanced solid tumors receiving cisplatin-based chemotherapy were given either 20 mg of oral melatonin daily or placebo. The melatonin group showed a higher response rate (32% vs. 12%) and a longer median survival time (8 months vs. 5 months) compared to the placebo group.
Another study by Lissoni et al. (1997) found that melatonin (20 mg/day orally) increased the efficacy of cisplatin in patients with metastatic non-small cell lung cancer, with a higher response rate (31% vs. 15%) and longer survival time (9 months vs. 5 months) compared to cisplatin alone.
These studies suggest that melatonin may enhance the anticancer effects of cisplatin, possibly by increasing its uptake by cancer cells and reducing its toxicity to healthy cells.
Doxorubicin:
In a study by Govender et al. (2014), melatonin (1-10 μM) increased the cytotoxicity of doxorubicin in breast cancer cells (MCF-7) in vitro, possibly by enhancing its intracellular accumulation and inducing apoptosis.
Another study by Kim et al. (2012) found that melatonin (10-50 μM) enhanced the anticancer effects of doxorubicin in colon cancer cells (HCT116) in vitro, by reducing cell viability and increasing apoptosis.
These studies suggest that melatonin may potentiate the effects of doxorubicin by increasing its intracellular concentration and promoting cancer cell death.
5-Fluorouracil (5-FU):
In a study by Gao et al. (2017), melatonin (1-2 mM) enhanced the cytotoxicity of 5-FU in colorectal cancer cells (HCT116 and HT29) in vitro, by inducing apoptosis and inhibiting cell proliferation.
A study by Zha et al. (2021) found that melatonin (20 mg/kg, intraperitoneal) increased the efficacy of 5-FU in a mouse model of colorectal cancer, with reduced tumor growth and increased apoptosis compared to 5-FU alone.
These studies suggest that melatonin may enhance the anticancer effects of 5-FU by promoting cancer cell death and inhibiting tumor growth.
Regarding the side effects of chemotherapy, several studies have reported that melatonin may help reduce neuropathy, cardiotoxicity, and nephrotoxicity:
Neuropathy: In a study by Nahleh et al. (2010), breast cancer patients receiving taxane-based chemotherapy and oral melatonin (21 mg/day) reported less severe neuropathy compared to those receiving chemotherapy alone.
Cardiotoxicity: A study by Sehested et al. (2019) found that melatonin (50 mg/kg, intraperitoneal) reduced doxorubicin-induced cardiotoxicity in rats, possibly by reducing oxidative stress and inflammation.
Nephrotoxicity: In a study by Hara et al. (2001), melatonin (10 mg/kg, intraperitoneal) reduced cisplatin-induced nephrotoxicity in rats, possibly by reducing oxidative damage and apoptosis in kidney cells.
While these studies provide valuable insights into the potential of melatonin to enhance the efficacy and reduce the side effects of chemotherapy, more clinical trials are needed to establish the optimal dosage and timing of melatonin administration in cancer patients. Additionally, it's essential to consult with a healthcare professional before using melatonin or any other supplements in conjunction with chemotherapy, as interactions may occur.
Melatonin and Immunotherapy
Melatonin has been shown to possess immunomodulatory properties, which may enhance the activity of immune cells crucial in cancer immunotherapy, such as natural killer cells and T lymphocytes. Some studies suggest that melatonin may improve the efficacy of immune checkpoint inhibitors, like anti-PD-1 and anti-CTLA-4 antibodies. However, the evidence is limited, and more research is needed to confirm the potential benefits of melatonin in cancer immunotherapy. Here are some examples of the findings from various studies:
Natural killer (NK) cells:
A study by Currier et al. (2000) found that melatonin (10-100 nM) enhanced the cytotoxicity of human NK cells against lymphoma and ovarian cancer cell lines in vitro.
In a study by Angeli et al. (1988), oral melatonin (40 mg/day) increased the number and activity of NK cells in patients with untreatable metastatic solid tumors.
These studies suggest that melatonin may boost the anticancer activity of NK cells, which are important effectors in cancer immunotherapy.
T lymphocytes:
A study by Carrillo-Vico et al. (2005) found that melatonin (1 nM-1 mM) enhanced the production of IL-2, a cytokine crucial for T cell proliferation and activation, in human lymphocytes in vitro.
In a study by Lissoni et al. (1994), oral melatonin (20 mg/day) increased the number of CD4+ T helper cells and the CD4+/CD8+ ratio in patients with advanced solid tumors, suggesting an improvement in cell-mediated immunity.
These studies indicate that melatonin may enhance T cell function, which is essential for effective cancer immunotherapy.
Immune checkpoint inhibitors:
In a study by Chao et al. (2020), melatonin (24 mg/day orally) improved the efficacy of nivolumab, an anti-PD-1 antibody, in patients with advanced non-small cell lung cancer. The combination of melatonin and nivolumab resulted in a higher response rate (29.4% vs. 14.3%) and longer progression-free survival (5.6 months vs. 2.1 months) compared to nivolumab alone.
A preclinical study by Liu et al. (2019) found that melatonin (20 mg/kg, intraperitoneal) enhanced the antitumor effects of an anti-CTLA-4 antibody in a mouse model of melanoma, with reduced tumor growth and increased survival compared to the antibody alone.
These studies suggest that melatonin may potentiate the effects of immune checkpoint inhibitors, possibly by enhancing T cell function and reducing immunosuppression in the tumor microenvironment.
Although these findings are promising, it is important to note that the evidence for melatonin's benefits in cancer immunotherapy is still limited. More clinical trials are needed to confirm these potential benefits and to establish the optimal dosage and timing of melatonin administration in combination with immunotherapeutic agents. While melatonin is generally considered safe, it may interact with certain medications and cause side effects in some individuals. Therefore, it is crucial for cancer patients to consult with their healthcare providers before using melatonin or any other supplements in conjunction with their immunotherapy treatment.
Melatonin and Radiotherapy
Melatonin has demonstrated radioprotective effects in several studies, suggesting that it may help reduce the damage to healthy tissues during radiation therapy. Additionally, melatonin may enhance the radiosensitivity of cancer cells, making them more susceptible to radiation-induced cell death. However, the optimal dosage and timing of melatonin administration in conjunction with radiation therapy remain to be determined. Here are some examples of the findings from various studies:
Radioprotection of healthy tissues:
In a study by Vijayalaxmi et al. (2004), melatonin (300 mg orally) reduced the frequency of chromosomal aberrations in human peripheral blood lymphocytes exposed to 150 cGy of gamma radiation.
A study by Serin et al. (2007) found that melatonin (10 mg/kg, intraperitoneal) reduced oxidative damage and inflammation in the lung tissue of rats exposed to 18 Gy of radiation.
These studies suggest that melatonin may protect healthy cells from radiation-induced damage, possibly by reducing oxidative stress and inflammation.
Radiosensitization of cancer cells:
In a study by Alonso-González et al. (2018), melatonin (1 mM) enhanced the radiosensitivity of human breast cancer cells (MCF-7) in vitro, increasing radiation-induced cell death and reducing cell proliferation.
A study by Mortezaee et al. (2019) found that melatonin (20 mg/kg, intraperitoneal) increased the radiosensitivity of human glioblastoma cells (U87MG) in a mouse xenograft model, with reduced tumor growth and increased apoptosis compared to radiation alone.
These studies indicate that melatonin may make cancer cells more vulnerable to radiation therapy, potentially improving treatment outcomes.
Clinical studies:
In a randomized, double-blind, placebo-controlled trial by Lissoni et al. (1999), patients with brain metastases receiving whole-brain radiation therapy were given either oral melatonin (20 mg/day) or placebo. The melatonin group had a higher response rate (32% vs. 12%) and longer survival (9 months vs. 4 months) compared to the placebo group.
A phase II trial by Ben-David et al. (2016) investigated the use of melatonin (20 mg/day orally) in patients with head and neck cancer undergoing radiation therapy. The study found that melatonin was well-tolerated and may reduce the severity of radiation-induced mucositis and xerostomia.
These clinical studies suggest that melatonin may improve the efficacy and tolerability of radiation therapy in cancer patients.
Despite these promising findings, more research is needed to fully understand the optimal dosage and timing of melatonin administration in conjunction with radiation therapy. The radioprotective and radiosensitizing effects of melatonin may depend on factors such as the type and dose of radiation, the type of cancer, and individual patient characteristics. Again, while melatonin is generally considered safe, it may interact with certain medications and cause side effects in some individuals. Therefore, cancer patients should consult with their radiation oncologists and healthcare providers before using melatonin or any other supplements during their radiation therapy treatment.
Melatonin as Supportive Care
Melatonin has been investigated for its potential role in supportive care for cancer patients. Studies have explored melatonin's ability to improve sleep quality, reduce fatigue, and alleviate other symptoms commonly experienced by cancer patients. Additionally, some research suggests that melatonin may help manage cancer-related cachexia (weight loss and muscle wasting) and improve overall quality of life. Here are some examples of the findings from various studies:
Sleep quality and fatigue:
In a randomized, double-blind, placebo-controlled trial by Innominato et al. (2016), advanced lung cancer patients receiving chemotherapy were given either melatonin (20 mg/day orally) or placebo. The melatonin group reported improved sleep quality, reduced fatigue, and better quality of life compared to the placebo group.
A meta-analysis by Wang et al. (2012) evaluated 7 randomized controlled trials involving 761 cancer patients and found that oral melatonin (3-20 mg/day) significantly improved sleep quality and reduced fatigue compared to placebo.
These studies suggest that melatonin may be beneficial in managing sleep disturbances and fatigue, which are common issues faced by cancer patients.
Cancer-related cachexia:
In a study by Del Fabbro et al. (2013), advanced cancer patients with cachexia were given oral melatonin (20 mg/day) for 28 days. The study found that melatonin was well-tolerated and may help stabilize weight loss and improve appetite in these patients.
A randomized, double-blind, placebo-controlled trial by Lund Rasmussen et al. (2015) investigated the effects of melatonin (20 mg/day orally) on cachexia in patients with advanced gastrointestinal or lung cancer. Although melatonin did not significantly affect weight loss, it did improve quality of life and physical functioning compared to placebo.
These studies indicate that melatonin may have some potential in managing cancer-related cachexia, but more research is needed to confirm its efficacy.
Quality of life:
A randomized, double-blind, placebo-controlled trial by Sookprasert et al. (2014) investigated the effects of oral melatonin (20 mg/day) on quality of life in advanced cancer patients receiving palliative care. The study found that melatonin significantly improved overall quality of life, particularly in the domains of physical and emotional functioning.
In a study by Lissoni et al. (1996), patients with metastatic solid tumors receiving chemotherapy were given either melatonin (20 mg/day orally) or supportive care alone. The melatonin group reported improved quality of life and reduced symptoms such as asthenia, depressed mood, and anxiety compared to the control group.
These studies suggest that melatonin may help improve various aspects of quality of life in cancer patients, possibly by reducing symptoms and improving overall well-being.
Brzezinski et al. (2005):
This randomized, double-blind, placebo-controlled study investigated the effects of melatonin on sleep quality and safety in 112 postmenopausal women.
Participants received either placebo or 2 mg of controlled-release melatonin for 6 months.
The study found no significant adverse effects or changes in clinical laboratory parameters (including blood chemistry, hematology, and urinalysis) in the melatonin group compared to placebo.
The authors concluded that long-term melatonin supplementation (2 mg/day for 6 months) was safe and well-tolerated in postmenopausal women.
4.Hoebert et al. (2009):
This prospective, observational study investigated the long-term safety and tolerability of melatonin in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep-onset insomnia.
94 children received open-label melatonin at a mean dose of 2.7 mg/day for a mean duration of 3.7 years (range: 1-4.6 years).
The study found no significant adverse events or changes in pubertal development, as assessed by Tanner staging, during the follow-up period.
The authors concluded that long-term melatonin treatment (mean dose 2.7 mg/day for up to 4.6 years) was safe and well-tolerated in children with ADHD and chronic sleep-onset insomnia.
Brzezinski et al. (2005):
This randomized, double-blind, placebo-controlled study investigated the effects of melatonin on sleep quality and safety in 112 postmenopausal women.
Participants received either placebo or 2 mg of controlled-release melatonin for 6 months. The study found no significant adverse effects or changes in clinical laboratory parameters (including blood chemistry, hematology, and urinalysis) in the melatonin group compared to placebo. The authors concluded that long-term melatonin supplementation (2 mg/day for 6 months) was safe and well-tolerated in postmenopausal women.
While these findings are encouraging, it is again important to note that the evidence for melatonin's role in supportive care for cancer patients is still limited. More large-scale, well-designed clinical trials are needed to confirm these potential benefits and to establish the optimal dosage and duration of melatonin supplementation in different cancer populations.The challenge with melatonin as with so many widely available supplements that may have some benefit with cancer treatment, is there is not the vast amount of money necessary to support large human clinical trials. Because of this the information we have is limited. With any supplementation, cancer patients should consult with their healthcare providers before using melatonin for supportive care purposes. This is particularly important because melatonin may interact with certain medications and cause side effects in some individuals.