Melatonin Disrupts Glioblastoma Metabolism and Enhances Temozolomide Cytotoxic Effects

INTRODUCTION: The resistance of glioblastoma to conventional therapies lies in a subpopulation of cells called Brain Tumor Initiating Cells, where the metabolic profile is highly dependent on aerobic glycolysis. Thus, a potential method to fight glioblastoma is by manipulating the metabolism of these cells. Reports have shown that high melatonin concentration displays oncostatic and chemotherapy adjuvant properties in several malignancies due to an increase in mitochondrial oxidative phosphorylation. Moreover, no side effects have been reported as a consequence of melatonin. METHODS: GBM patient-derived cell lines were treated with melatonin at 1.5 or 3 mM alone or in combination with TMZ 0.7 or 3 mM for 48 h. Proliferation assays, migration, apoptosis, cell cycle were evaluated. Metabolic shift through seahorse and RT-PCR analysis. RESULTS: Treatment of GBM cell lines with 3 mM melatonin in vitro resulted in decreased proliferative (P < .001), migratory (P < .005), and invasive capacity. Furthermore, an increase in early apoptosis was observed after 48 hs (P < .05), along with an arrest in G2M and a drop in cells in S phase. Also a significant intracellular accumulation of lactate was observed, while decreasing in the extracellular media, which was explained by the reduction in the expression of the lactate symporter MCT4, CD147 transmembrane marker and the downregulation of main enzymes involved on the aerobic glycolysis. These effects were compensated by an increase in the oxygen consumption rate. Metabolic shift was confirmed by the increment in mitochondrial ROS production (P < .001), eventually leading to cell differentiation. Thus, the cells became more sensitive to TMZ, which we have found synergizes with melatonin (P < .001). CONCLUSION: Our results show that disrupting BTIC metabolism with melatonin leads to cell dead and by chemosensitizing them, it would allow a reduction in TMZ dosage, therefore decreasing possible side-effects and indicating melatonin as a strong therapeutic candidate for GBM therapy.