Different Effects of Melatonin on X-Rays-Irradiated Cancer Cells in a Dose-Dependent Manner

Abstract

The purpose of this study is to investigate the effects of melatonin on the radiosensitivity of HeLa cells. Concentration from 10 to 1000 µM of melatonin was used on HeLa cells before X-rays irradiation (IR). The cellular inactivation effect was analyzed by clonogenic assay, and cell growth was measured by MTT assay at various concentrations. Ten micrometer melatonin promoted the cell-killing effects of IR, while 1000-µM melatonin prevented IR-induced cellular inactivation. Further analysis revealed that 1000-µM melatonin protected the cells from IR-induced reactive oxygen species damage, as the oxidative stress measured by fluorescent microscopy and fluorescence-activated cell sorting using 2,7-dichlorofluorescein diacetate staining. This is further confirmed by melatonin receptor agonist, which has no antioxidant capacity. A 10-µM melatonin, on the contrary, enhanced the cell-killing effects of IR by activating c-Jun NH2-terminal kinase (JNK) signaling. c-Jun NH2-terminal kinase signaling activation was indicated by Western blot of phosphorylated JNK. We used JNK inhibitor to further confirm the involvement of JNK signaling in the cell-killing enhancement of 10-µM melatonin administration. Our results suggest the importance of dose-dependent effects in melatonin application for radiotherapy.

Melatonin Modulation of Radiation-Induced Molecular Changes in MCF-7 Human Breast Cancer Cells

“…Specifically, when combined with radiotherapy, melatonin enhances cancer cell damage by increasing the radiation sensitivity of tumor cells, simultaneously protecting nontumor tissues from the deleterious effects of this treatment. There are a variety of mechanisms by which melatonin potentiates the effects of radiation; among them, the pineal hormone enhances the acute cytotoxic effects of radiation by increasing the production of intracellular reactive oxygen species (ROS) [10]. In human breast cancer cells, the administration of melatonin as a previous step to radiation showed a radiosensitizing effect associated with a decrease in the synthesis of the enzymes responsible for estrogen biosynthesis [11].…”

Melatonin as a Radio-Sensitizer in Cancer

“…Melatonin potentiates laser irradiation effects by stimulation of free-radical mediated apoptosis [ 53 ]. In human cervical cancer cells, the effects of melatonin on the radiosensitivity are dose-dependent and a concentration of 10 μM enhances the cell-killing effect of X-rays irradiation, mediated by an increase in ROS induced by melatonin, whereas 1 mM concentration neutralizes X-rays irradiation-induced cell inactivation [ 54 ].…”

“…Melatonin, contrary to what happens in normal cells where it has anti-apoptotic actions, potentiates apoptosis in malignant cells. In ovarian cancer cells, melatonin enhances the apoptosis induced by laser irradiation [ 54 ]. Melatonin sensitization of cancer cells to the induction of apoptosis after ionizing radiation is performed through several mechanisms, which have been summarized in a recent review [ 70 ].…”