Melatonin as a Radio-Sensitizer in Cancer

Abstract

Radiotherapy is one of the treatments of choice in many types of cancer. Adjuvant treatments to radiotherapy try, on one hand, to enhance the response of tumor cells to radiation and, on the other hand, to reduce the side effects to normal cells. Radiosensitizers are agents that increase the effect of radiation in tumor cells by trying not to increase side effects in normal tissues. Melatonin is a hormone produced mainly by the pineal gland which has an important role in the regulation of cancer growth, especially in hormone-dependent mammary tumors. Different studies have showed that melatonin administered with radiotherapy is able to enhance its therapeutic effects and can protect normal cells against side effects of this treatment. Several mechanisms are involved in the radiosensitization induced by melatonin: increase of reactive oxygen species production, modulation of proteins involved in estrogen biosynthesis, impairment of tumor cells to DNA repair, modulation of angiogenesis, abolition of inflammation, induction of apoptosis, stimulation of preadipocytes differentiation and modulation of metabolism. At this moment, there are very few clinical trials that study the therapeutic usefulness to associate melatonin and radiotherapy in humans. All findings point to melatonin as an effective adjuvant molecule to radiotherapy in cancer treatment.

Melatonin as an Oncostatic Molecule Based on Its Anti-Aromatase Role in Breast Cancer

“…Since estrogens play a role in breast cancer growth, the estrogen signaling pathway has become a main focus of cancer therapy. In order to neutralize the effects of estrogens, melatonin could be utilized as it regulates the enzymes responsible for local estrogen synthesis [ 28 ]. In human mammary tumors, aromatase, sulfatase, and 17β-HSD1, which are in charge of converting androgens into estrogens, hydrolyzing estrone sulfates to estrone, and transforming estrone to the potent 17β-estradiol, respectively, are reportedly overexpressed [ 48 ].…”

“…In contrast, estrogen sulfotransferase tends to be decreased, presumably leading to the accumulation of 17β-estradiol in mammary tumor tissue [ 48 ]. Since estrogen sulfotransferase is an enzyme that inactivates 17β-estradiol, the levels of 17β-estradiol in mammary tumor tissue are increased [ 28 , 57 ]. Interestingly, melatonin reduces the activity of aromatase, sulfatase, and 17β-HSD1, and increases estrogen sulfotransferase expression, followed by declining estrogenic effects [ 48 , 57 , 58 ].…”

“…Therefore, researchers have concentrated on how to reduce the harmful side effects on normal tissues. Several studies have insisted that melatonin is able to enhance the therapeutic effect of radiation and simultaneously protect non-cancerous cells from side effects following radiotherapy [ 28 ]. Indeed, melatonin has been proven to potentiate the inhibitory effect of radiation on aromatase expression and activity.…”

“…Intriguingly, aromatase activity in breast cancer cells is known to be regulated by melatonin [ 26 , 27 ]. It lowers estrogen biosynthesis by suppressing aromatase activity [ 28 ]. Multiple researchers have found receptor-targeted cancer therapies to be effective, and their transaction with melatonin would be beneficial [ 29 , 30 ].…”

A review on radiation induced nausea and vomiting: “Current management strategies and prominence of radio sensitizers”

“…41 The use of melatonin in various cancers with radiotherapy increases the cytotoxic effect of radiations and reduce the DNA repair capacity of tumour cells. 42 Mostly tumour cells with hypoxia, low oxygen and nutritional states are resistant to radiotherapy hence radio sensitizers provide an additive effects and prevent the radiation resistance of tumour cells. 43 This field of nanotechnology used as radio sensitizers enhances the selective sensitivity of tumour cells and sets the normal cells free of damage.…”