Protective effect of melatonin on oxaliplatin-induced apoptosis through sustained Mcl-1 expression and anti-oxidant action in renal carcinoma Caki cells.
Melatonin is an indolamine initially found to be produced in the pineal gland but now known to be synthesized in a variety of other tissues as well. The mechanisms whereby melatonin regulates the apoptotic program remain only partially understood. Anti-/pro-apoptotic effects of exogenous melatonin on various stimuli-mediated apoptosis were investigated in this report. We investigated the combined effect of melatonin and death receptor-mediated ligands (TNF-α, TRAIL, and anti-Fas antibody) or endoplasmic reticulum (ER) stress-inducing agents (thapsigargin, brefeldin A, and tunicamycin) on apoptosis of cancer cells. Death receptor- or ER stress-induced apoptosis was not significantly influenced by melatonin treatment. However, pretreatment with melatonin significantly inhibited DNA damage-induced apoptosis and glutathione (GSH) depletion, suggesting the reactive oxygen species mediate oxaliplatin/etoposide-induced apoptosis. Interestingly, we also found the involvement of myeloid cell leukemia-1 (Mcl-1) downregulation in oxaliplatin-induced apoptosis; thus, pretreatment with melatonin inhibited Mcl-1 downregulation, and ectopic expression of Mcl-1 attenuated oxaliplatin-induced apoptosis. Taken together, the results demonstrate that melatonin attenuates oxaliplatin-induced apoptosis in cancer cells by inhibition of GSH depletion and Mcl-1 downregulation.
Um
Hee Jung
HJ
Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu, Korea.
Kwon
Taeg Kyu
TK
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D005978:Glutathione; D008550:Melatonin