The pineal gland in the brain discharges the hormone melatonin, whose secretion during times of darkness represents a 24-hour rhythm regulated by the circadian clock and is pivotal in regulating sleep and wake cycles. Circadian rhythms are endogenous processes and can be influenced by environmental factors such as light and temperature. Additionally, melatonin has also been witnessed to function in the immune system, female menstrual cycles, seasonal behavior, tumor inhibition, and anti-aging processes. Melatonin generation increases during the night and decreases in the daytime with a presentation to light. Cheap levels of regular melatonin have been associated with neoplasia, such as the growth of rat hepatomas, human breast cancer xenografts, circadian phase shifts, sleep disturbances, plus immunosuppression. Moreover, sleep disturbance, not factoring in melatonin generation, can lead to immune suppression and a change to the predominance in cancer-stimulatory cytokines. Based on investigations, melatonin significantly contains cell proliferation and induces apoptosis.
INTRODUCTION
Melatonin, N-acetyl-5-methoxytryptamine, is an indolic compound emitted primarily by the pineal gland of humans and mammals in acknowledgment of darkness. But for the pineal, melatonin production is also found in many other organs, like the retina, gastrointestinal tract, skin, bone marrow, and lymphocytes.
Now, patients with cancer primarily count on clinical treatment, like surgery, radiotherapy, and chemotherapy. In addition, some natural products revealed the potential for cancer prevention and cancer treatment. Studies on cancer and anticancer therapies have drawn significant attention.
In the last decades, expanding evidence has outlined the pertinence of melatonin to human physiology and pathology. It is well accepted that melatonin is a hormone and a cell protector involved in immunomodulation, antioxidative processes, and hematopoiesis. Besides, many studies have shown that melatonin has extensive oncostatin properties through receptor-dependent and receptor-independent mechanisms.
Many epidemiological studies establish a protective role of melatonin in cancer, yet not all epidemiological studies are compatible. Some studies proposed an inverse association linking circadian melatonin level and breast cancer incidence.
MELATONIN IN CANCER DEVELOPMENT
Melatonin has been recognized to affect tumor growth, and its secretion corresponds with light and a circadian rhythm. The relationship betwixt melatonin secretion, light, and cancer suggests that an improvement in the prevalence of various types of cancer agrees with industrialization and exposure to more kinds of artificial light, thus resulting in weaker levels of nocturnal melatonin. In animals, pineal suppression and pinealectomies incite the growth and metastasis of experimental lung cancer, liver cancer, ovarian cancer, pituitary cancer, and prostate cancer.
Clinical evidence and research have also given the future use of melatonin to treat breast cancer patients. Shreds of evidence found that in women with breast cancer, the melatonin levels both in the morning and evening were unnatural. Nocturnal melatonin levels were faint, while morning urine samples of breast cancer patients displayed high MEL levels, opposite what is expected in healthy individuals.
Melatonin has also been confirmed to improve survival rates in sufferers of prostate and colorectal cancer. Studies have shown that men with first localized malignant prostate tumors have shallow levels of nocturnal melatonin that decrease with an advance in tumor growth. Subjects with unoperated colorectal carcinoma had significantly lower nocturnal plasma melatonin levels compared to controls.
Besides, melatonin has been shown to hinder the overproduction of estradiol, which provokes the cell division of breast cells. Although several melatonin-cancer studies have given enough data to suggest a correlation linking melatonin levels and cancer risk, different studies have also found results inimical to this hypothesis.
MELATONIN AND BREAST CANCER
Breast cancer, the most prevailing cancer in gentlewomen, is one of the leading causes of demise for women aged 40 to 55.
Melatonin manifested an anti-metastatic effect on CMT-U229, and MCF-7 breast cancer cell lines by inhibiting breast cancer Mammo spheres’ viability and invasiveness and interceding presence of epithelial-mesenchymal transition (EMT) related proteins. It has been proved that melatonin might manage tumor growth in advanced cancer patients, which was at most limited in part through functioning as a natural anti-angiogenic molecule as evidenced by limited blood VEGF levels.
Melatonin can also inhibit aromatase action in breast cancer cells.
The synergetic impact of melatonin with other anticancer drugs or radiotherapy is also exceptional.
Various studies published the synergetic effect of melatonin with different anticancer agents on breast cancer. Melatonin co-administration significantly enlarged the pro-differentiating, anti-proliferative, and immunomodulatory exercises presented by Lactobacillus plantarum and inulin.
Collectively, melatonin has presented an inhibitory effect on both ER-positive and ER-negative breast cancers. Melatonin’s anti-breast cancer effect was mediated by its interaction with estrogen receptors and the melatonin receptors and activating various receptor-independent and estrogen-independent signaling pathways. Given the broad spectrum of melatonin’s action on breast cancer, united with its low toxicity, it could be considered a potential therapeutic choice for preventing and treating breast cancer.
MELATONIN AND PROSTATE CANCER
Prostate cancer is the second most usually occurred cancer and the fifth foremost cause of cancer mortality in men.
Melatonin significantly suppressed angiogenesis-related proteins HIF-1α, HIF-2α, and VEGF at mRNA level of PC-3 cells under hypoxia, and upregulation of miRNA3195 and miRNA374b could negotiate this anti-angiogenic property of melatonin. Besides, melatonin represented anti-proliferative consequences on prostate cancer cell lines, LNCaP, and 22Rv1.
Daytime blue light could improve nocturnal melatonin and then intensify the inhibition on human prostate cancer growth on male nude rats, as shown by reduced tumor growth rates, tumor cAMP levels, aerobic glycolysis (called Warburg effect), uptake-metabolism of linoleic acid, and growth signaling activities.
These scientific pieces of literature collectively support the potential application of melatonin to prevent and treat prostate cancer. Notably, melatonin could exert anti-proliferative exercise on androgen-independent prostate cancer cells (e.g. PC-3 cells), making melatonin a clinical decision to postpone the relapse of hormone-refractory or castration-resistant prostate cancer in union with androgen deprivation therapy.
MELATONIN AND OVARIAN CANCER
Ovarian cancer is one of the principal causes of death among women with genital tract dysfunctions.
Melatonin provoked an accumulation of OVCAR-429 and PA-1 ovarian cancer cells in the G1 phase through downregulation of CDK 2 and 4.
A group scrutinized the oncostatin effect of melatonin on ovarian cancer applying an ethanol-preferring rat model. The left ovary was inoculated with an ovarian tumor, and the right ovary was used as the sham-surgery control. They discovered that melatonin could overcome ovarian tumor masses and lower the incidence of adenocarcinoma in rats. Next, they investigated the apoptosis-promoting impression of melatonin on ovarian cancer. Conclusions showed that absolute and relative tumor masses were significantly reduced after melatonin therapy, notwithstanding ethanol consumption.
Collectively, melatonin has given anticancer effect on ovarian cancer, and the underlying mechanisms include effecting apoptosis and cell cycle arrest, and immunoregulation (toll-like receptors).
MELATONIN AND CERVICAL CANCER
Cervical cancer is the second preeminent cause of female tumors globally, and its incidence in emerging countries is much higher than that in advanced countries. The anticancer impact of melatonin on cervical cancer has been published in a few studies.
Melatonin could decrease cervical cancer cell viability in vitro and defeat cervical adenocarcinoma metabolism in vivo. More studies are required to adequately explain the oncostatin effect of melatonin on cervical cancer and assist the clinical application of melatonin.
MELATONIN AND ORAL CANCER
Oral cancer is a general type of human head and neck cancer, and most of the cases involve oral squamous cell carcinoma. In some in vitro studies, melatonin has shown a remarkable effect on oral cancer.
In a study, melatonin performed an anti-metastatic effect on oral cancer cell lines (HSC-3 and OECM-1) by attenuating MMP-9 expression and activity, which was mediated by lowering histone acetylation. Besides, melatonin could limit the cell viabilities of SCC9 and SCC25 cell lines (both squamous cell carcinoma of the tongue) and exert an inhibitory effect on pro-metastatic gene expression ROCK-1 pro-angiogenic genes, HIF-1α and VEGF in SCC9 cell line.
Melatonin has collectively shown an inhibitory effect on some oral cancer cells, and the underlying mechanisms mainly involved inhibition of metastasis and angiogenesis.
MELATONIN AND LIVER CANCER
Liver cancer is the second most prevalent cause of cancer death worldwide, and hepatocellular carcinoma (HCC) is the main kind of liver cancer (70%-80%), which is one of the most common cancers with the highest incidence in developing countries. Surgery remains the most effective treatment for patients with HCC, but it only fits limited cases. Thus, finding efficient chemotherapeutic drugs is required. The effects of melatonin on liver cancer have been summarized in several studies.
A study exposed the underlying mechanism of melatonin’s anti-invasive action in HepG2 liver cancer cells by defeating MMP-9 gelatinase activity, downregulating MMP-9 gene character, and upregulation of tissue inhibitors metalloproteinases (TIMP)-1 and pressing NF-κB translocation and transcriptional activity. Besides, melatonin also showed anti-angiogenic outcomes on HepG2 liver cancer cells by interfering with the transcriptional activation of VEGF, diminishing Hif1α protein expression and STAT3 action.
In a study, melatonin inverted the alteration caused by N-nitrosodiethylamine-induced liver tumor in liver marker enzymes (ALT, AST), antioxidant levels, and circadian clock disturbance in mice. Another study proposed that melatonin attenuated hepatocarcinogenesis caused by diethylnitrosamine in rats by stimulating ER stress and inducing apoptosis.
Collectively, melatonin could inhibit the process of hepatocarcinogenesis mainly through the pro-apoptotic (via modulation of COX-2/PI3K/AKT pathway, Bcl-2/Bax ratio, activation of ER stress), anti-angiogenesis, and anti-invasive effects.
MELATONIN AND LUNG CANCER
Lung cancer is another leading cause of cancer-related demises.
Non-small-cell lung cancer (NSCLC) is an effective form of lung cancer, and the published literature has advised that the disruption of melatonin rhythm could develop the NSCLC incidence. In many studies, melatonin has been related to being a potential therapeutic strategy for lung cancer, chiefly because melatonin enhances the effects of radiotherapy and some anticancer drugs.
It concluded from the available evidence that melatonin’s influence was more significant when used as an adjuvant therapy than being used alone for lung cancer. The intensification of melatonin on the therapeutic effects of gefitinib, berberine, and doxorubicin demonstrated its beneficial role in preventing and treating lung cancer.
MELATONIN AND GASTRIC CANCER
Gastric cancer is one of the most typical forms of cancer globally and causes a mortality rate ranking second amongst malignant tumors worldwide.
It has come to be known that melatonin inhibited HIF-1α accumulation and endogenous VEGF generation by inhibition of RZR/RORγ in hypoxic SGC-7901 cells, thus restraining the proliferation of gastric cancer cells. Also, melatonin inhibited angiogenesis in the SGC-7901 gastric cancer cell line, as illustrated by decreased VEGF mRNA and protein expression. It suppressed the expression of nuclear receptor RZR/RORγ mRNA and protein. In addition, melatonin inhibited cell viability, clone formation, cell migration, and invasion, and induced apoptosis of AGS gastric cancer cell line through the activation of JNK and P38 MAPK and the suppression of NF-κB. Besides, melatonin significantly potentiated the anti-tumor effect of cisplatin with weak systemic toxicity.
A study found that melatonin-induced C/EBPβ and NF-κB suppression could block gastric tumor growth and peritoneal dissemination through inhibiting EMT and inducing ER tension. Additionally, melatonin lessened the tumor volume and weight of tumors in gastric tumor-bearing nude mice. It inhibited proliferation and angiogenesis by suppressing the expression of RZR/RORγ, Sentrin-specific protease 1 (SENP1), HIF-1α, and VEGF.
Overall, melatonin has manifested a striking inhibitory effect on the growth of gastric cancer cells. The underlying mechanisms mainly comprised of inhibiting angiogenesis, enhancing apoptosis, and immunoregulation effect.
OTHERS
Melatonin has exhibited remarkable effects against the cancers mentioned earlier, but it is also equally efficient against pancreatic cancer, colorectal cancer, melanoma, and pituitary prolactin-secreting tumor.
CONCLUSION
Clinical trials utilizing melatonin as an anti-cancer regimen and studies conducted on the role of melatonin in the prevention of cancer development reveal the surging potential of melatonin as a therapeutic medication to battle sleep disorders, cancer, and the side effects of chemotherapy. As observed in both animals and humans, melatonin has a deficient level of toxicity, and even in relatively high doses, it typically does not cause significant side effects. However, unimportant side effects include headaches, dizziness, drowsiness, and nausea, and apathy combined with weight gain. However, melatonin treatment in children can be nurtured long-term without severe deviations of normal development, such as sleep quality, puberty, and mental health.
Through a range of apoptosis pathways and interplays with the immune system, chemotherapy, and anti-cancer drugs, melatonin can increase tumor regression in cancer patients. Melatonin has been shown to provoke many positive effects to defend the body and cells from damage. Still, improper administration can culminate in hazardous products, including the stimulation of tumor growth.
Shortly, several aspects of melatonin’s anticancer action should be further reviewed.
