The Therapeutic Potential of Melatonin: A Review of the Science

Samir Malhotra, MD; Girish Sawhney, MD; Promila Pandhi, MD

Disclosures
In This Article

Cancer

It has been suggested that the steady rise in the incidence of cancer in developed countries during the last 100 years is caused by the routine, artificial extension of the photoperiod by electric lights, or "light pollution."[40] A long photoperiod results in depressed melatonin secretion during the night. In animals, melatonin inhibits the incidence of chemically induced tumors, which is increased by pineal suppression (long light phase) or pinealectomy.[41] Pinealectomy stimulates and/or melatonin inhibits the growth and sometimes the metastasis of experimental cancers of the lung, liver, ovary, pituitary, and prostate as well as melanoma and leukemia.[42]

Breast cancer

Clinical evidence suggests a role for melatonin in the prevention and even the treatment of breast cancer.[43] For example, the circadian amplitude of melatonin was reduced by more than 50% in patients with breast cancer vs patients with nonmalignant breast disease,[44] and high melatonin levels have been found in morning urine samples of breast cancer patients,[45] suggesting circadian disorganization. Melatonin downregulates estrogen receptors; inhibits estrogen-stimulated, breast cancer growth; and complements the oncostatic action of antiestrogen drugs (tamoxifen), leading to the suggestion that melatonin is a 'natural antiestrogen.'[46] Moreover, a synergy has been demonstrated between melatonin and all-trans-retinoic acid (ATRA), allowing the use of lower doses of ATRA and thus avoiding its adverse effects.[47]

The molecular mechanisms of melatonin have also begun to be better understood. Melatonin has been shown to shift forskolin- and estrogen-induced elevation of cyclic adenosine monophosphate (cAMP) levels by 57% and 45%, respectively,[48] thereby affecting signal-transduction mechanisms in human breast cancer cells.

Anisimov and coworkers[49] have found that constant treatment with melatonin reduced the incidence and size of breast carcinomas as well as lowered the incidence of lung metastasis, but interrupted treatment-promoted, mammary carcinogenesis in transgenic mice. They further observed that the life span of the group receiving interrupted treatment was shorter; however, this outcome could be attributed to the transgenic nature of mice used, but this needs further evaluation.

Prostate and Colorectal Cancers

Melatonin may also play a special role in prostate and colorectal cancers. Circadian amplitude of melatonin is reduced by two thirds in patients with prostate cancer as compared with those who have benign prostate disease,[44] and similar phenomena have been observed in patients with colorectal cancer.[50] In prostatic carcinoma, melatonin exerts complex interactions with androgen receptors and affects intracellular trafficking; melatonin does not affect cell growth in the absence of dihydrotesterone.[51] In 1 study, 54 patients with metastatic solid tumors, primarily lung and colorectal, received intramuscular melatonin, 20 mg daily at 3 pm for 2 months and then 10 mg daily. This regimen resulted in stabilization of the disease and improved quality of life for about 40% of the recipients.[52] The antiproliferative and proapoptotic actions of melatonin on experimental colon carcinoma are probably mediated by melatonin MT(1) and MT(2) receptors.[53]

In another study, melatonin 10-50 mg daily at 8 pm potentiated IL-2 immunotherapy of pulmonary metastases.[33] As with melatonin therapy in patients with AIDS, the study encouraged treatment periods of 3-4 weeks with a 1-week washout.

Melatonin injections have been found to stimulate tumor growth if given in the morning, have no effect when given in midafternoon, and have a retarding effect in the evening.[45,46]

Some have suggested that melatonin be administered to patients at earlier stages of cancer, in parallel with standard oncologic treatment regimens.[54] However, some questions remain concerning the anticancer effects of melatonin,[55] and data from stringent, large, randomized clinical trials are required before melatonin can be universally accepted as an anticancer drug.

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