Melatonin suppresses doxorubicin-induced premature senescence of A549 lung cancer cells by ameliorating mitochondrial dysfunction.

Abstract

Melatonin is an indolamine that is synthesized in the pineal gland and shows a wide range of physiological functions. Although the anti-aging properties of melatonin have been reported in a senescence-accelerated mouse model, whether melatonin modulates cellular senescence has not been determined. In this study, we examined the effect of melatonin on anticancer drug-induced cellular premature senescence. We found that the doxorubicin (DOX)-induced senescence of A549 human lung cancer cells and IMR90 normal lung cells was substantially inhibited by cotreatment with melatonin in a dose-dependent manner. Mechanistically, the DOX-induced G2/M phase cell cycle arrest and the decrease in cyclinB and cdc2 expression were not affected by melatonin. However, the DOX-induced increase in intracellular levels of ROS, which is necessary for premature senescence, was completely abolished upon melatonin cotreatment. In addition, the reduction in mitochondrial membrane potential that occurs upon DOX treatment was inhibited by melatonin. An aberrant increase in mitochondrial respiration was also significantly suppressed by melatonin, indicating that melatonin ameliorates the mitochondrial dysfunction induced by DOX treatment. The treatment of A549 cells with luzindole, a potent inhibitor of melatonin receptors, failed to prevent the effects of melatonin treatment on mitochondrial functions and premature senescence in cells also treated with DOX; this suggests that melatonin suppresses DOX-induced senescence in a melatonin receptor-independent manner. Together, these results reveal that melatonin has an inhibitory effect of melatonin on premature senescence at the cellular level and that melatonin protects A549 cells from DOX-induced senescence. Thus, melatonin might have the therapeutic potential to prevent the side effects of anticancer drug therapy.

• Authors: Naree Song, Ae Jeong Kim, Hyun-Ju Kim, Hye Jin Jee, Minjee Kim, Young Hyun Yoo, Jeanho Yun
• Journal: Journal of pineal research (J Pineal Res) Vol. 53 Issue 4 Pg. 335-43 (Nov 2012) ISSN: 1600-079X [Electronic] England
• PMID: 22536785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 John Wiley & Sons A/S.

Chemical References

• Antibiotics, Antineoplastic
• Cyclin B
• Reactive Oxygen Species
• Receptors, Melatonin
• Tryptamines
• luzindole
• Doxorubicin
• CDC2 Protein Kinase
• CDK1 protein, human
• Cyclin-Dependent Kinases
• Melatonin

Topics

• Antibiotics, Antineoplastic (pharmacology)
• CDC2 Protein Kinase
• Cell Line, Tumor
• Cellular Senescence (drug effects)
• Cyclin B (metabolism)
• Cyclin-Dependent Kinases
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Lung Neoplasms (metabolism, pathology)
• Melatonin (pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Receptors, Melatonin (drug effects, metabolism)
• Time Factors
• Tryptamines (pharmacology)