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-alpha, 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.