Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

Abstract

Effective drug combinations have the potential to strengthen therapeutic efficacy and combat drug resistance. Both melatonin and valproic acid ( VPA ) exhibit antitumor activities in various cancer cells. The aim of this study was to evaluate the cell death pathways initiated by anticancer combinatorial effects of melatonin and VPA in bladder cancer cells. The results demonstrated that the combination of melatonin and VPA leads to significant synergistic growth inhibition of UC 3 bladder cancer cells. Gene expression studies revealed that cotreatment with melatonin and VPA triggered the up‐regulation of certain genes related to apoptosis ( TNFRSF 10A and TNFRSF 10B), autophagy ( BECN , ATG 3 and ATG 5) and necrosis ( MLKL , PARP ‐1 and RIPK 1). The combinatorial treatment increased the expression of endoplasmic reticulum ( ER )‐stress‐related genes ATF 6, IRE 1, EDEM 1 and ER dj4. Cotreatment with melatonin and VPA enhanced the expression of E‐cadherin, and decreased the expression of N ‐cadherin, Fibronectin, Snail and Slug. Furthermore, the Wnt pathway and Raf/ MEK / ERK pathway were activated by combinatorial treatment. However, the effects on the expression of certain genes were not further enhanced in cells following combinatorial treatment in comparison to individual treatment of melatonin or VPA . In summary, these findings provided evidence that cotreatment with melatonin and VPA exerted increased cytotoxicity by regulating cell death pathways in UC 3 bladder cancer cells, but the clinical significance of combinatorial treatment still needs to be further exploited.