Melatonin Sensitize the Ovarian Cancer Cells to Cisplatin through suppression of PI3K/Akt pathway

Abstract Background: The present study elucidated the effect of melatonin on oxidative stress status, the expression of pro-apoptotic protein (caspase 3 and cleaved caspase 3), anti-apoptotic proteins (X-linked apoptosis inhibitor protein (XIAP) and Survivin), and the activity of PI3K/Akt signaling pathway in human ovarian cancer cell line.Methods: Human ovarian cancer cells (OVCAR3) were treated with cisplatin, melatonin, cisplatin + melatonin, and siRNA Akt. Reactive oxygen species (ROS) levels were assessed using fluorimetric assay in the different groups. Moreover, protein expression of caspase-3, cleaved caspase 3, PI3K, Akt, phosphorylated (p)-Akt, XIAP, and Survivin were determined by Western blotting in all experimental groups.Results: Our results showed that administration of melatonin significantly increased intracellular ROS generation, the cleavage of caspase 3 and phosphorylation of Akt. This effect was more prominent in the combination therapy with cisplatin versus cisplatin alone. Akt siRNA transfection had similar effects on ROS generation, the cleavage of caspase 3, and phosphorylation of Akt. Interestingly, the levels of XIAP, PI3K, and Survivin were not significantly changed by any of these treatments.Conclusions: Taken together, this study suggests that combination therapy of cisplatin and melatonin increases apoptosis in the OVCAR-3 cells by inhibition of PI3K/Akt signaling pathway and exacerbation of oxidative stress.