Protective effect of melatonin on oxaliplatin-induced apoptosis through sustained Mcl-1 expression and anti-oxidant action in renal carcinoma Caki cells

Abstract

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.