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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.

Melatonin has recently gained attention as a regulator of biologic processes in addition to its effects on circadian rhythms. The mechanisms whereby melatonin regulates the apoptotic program remain poorly understood. In this study, we investigated the combined effect of melatonin and kahweol on apoptosis of cancer cells, but not in most normal human cell types, thus presenting an attractive novel strategy for cancer treatment. In our experiments, treatment with a combination of melatonin and kahweol induced apoptosis, stimulated DEVDase activity, and DNA fragmentation. Co-treatment with melatonin and kahweol induced up-regulation of p53-upregulated modulator of apoptosis (PUMA) while down-regulation of PUMA expression using small interfering RNAs attenuated melatonin plus kahweol-induced apoptosis. In addition, co-treatment with kahweol and melatonin induced PUMA up-regulation through endoplasmic reticulum stress-mediated C/EBP homologous protein induction and the p53-independent pathway. Our results collectively demonstrate that up-regulation of PUMA contributes to the sensitizing effect of melatonin plus kahweol on apoptosis in cancer cells.