Melatonin Prevents Mitochondrial Damage Induced by Doxorubicin in Mouse Fibroblasts Through Ampk-Ppar Gamma-Dependent Mechanisms
Celal Guven, Eylem Taskin, Handan Akcakaya
(Department of Biophysics, Faculty of Medicine, University of Adiyaman, Adiyaman, Turkey)
Med Sci Monit 2016; 22:438-446
Doxorubicin (brand name: Adriamycin®) is used to treat solid tissue cancer but it also affects noncancerous tissues. Its mechanism of cytotoxicity is probably related to increased oxidation, mitochondrial dysfunction, and apoptosis. Melatonin is reported to have antiapoptotic and antioxidative effects. The aim of this study was to determine whether melatonin would counteract in vitro cytotoxicity of doxorubicin in mouse fibroblasts and determine the pathway of its action against doxorubicin-induced apoptosis.
MATERIAL AND METHODS: We measured markers of apoptosis (cytochrome-c, mitochondrial membrane potential, and apoptotic cell number) and oxidative stress (total oxidant and antioxidant status) and calculated oxidant stress index in 4 groups of fibroblasts: controls, melatonin-treated, doxorubicin-treated, and fibroblasts concomittantly treated with a combination of melatonin and doxorubicin.
RESULTS: Melatonin given with doxorubicin succesfully countered apoptosis generated by doxorubicin alone, which points to its potential as a protective agent against cell death in doxorubicin chemotherapy. This also implies that patients should be receiving doxorubicin treatment when their physiological level of melatonin is at its highest, which is early in the morning.
CONCLUSIONS: This physiological level may not be high enough to overcome doxorubicin-induced oxidative stress, but adjuvant melatonin treatment may improve quality of life. Further research is needed to verify our findings.
Keywords: Animals, AMP-Activated Protein Kinases - metabolism, Antioxidants - pharmacology, Apoptosis - drug effects, Caspase 3 - metabolism, Cell Survival - drug effects, Cytochromes c - metabolism, Doxorubicin - toxicity, Drug Interactions, Fibroblasts - metabolism, Melatonin - pharmacology, Membrane Potential, Mitochondrial - drug effects, Mice, Mitochondria - metabolism, NIH 3T3 Cells, Oxidative Stress - drug effects, PPAR gamma - metabolism