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.

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Cisplatin (DDP)-based chemotherapy remains one of the standard treatment options for patients with advanced lung adenocarcinoma (LUAD), and cisplatin resistance is the biggest challenge to this therapy. Autophagy is also closely associated with chemoresistance in LUAD. Desperately need to find a way to improve the treatment efficiency of cisplatin-resistant LUAD in clinical practice. Previous studies reported that methylseleninic acid (MSA) has good anti-proliferation and pro-apoptotic activities in tumor cells. However, the effectiveness of MSA on cisplatin-resistant LUAD and its effect on the induction of autophagy is still unclear. In the current study, we found that MSA effectively inhibited the proliferation of LUAD cell lines and triggered mitochondrial pathway-mediated apoptosis. This effect was more pronounced in cisplatin-resistant LUAD cells with high MDR1 expression. In contrast, the mitochondrial damage caused by MSA treatment can be degraded by inducing selective autophagy in LUAD cells, thereby exerting a self-protective effect on tumor cells. Mechanistically, MSA inhibits proliferation, promotes apoptosis, and induces autophagy in LUAD cells by inhibiting of the Akt/mTOR pathway. Combination with autophagy inhibitors reduces the effect of this selective autophagy-induced resistance, and thus enhancing even more the anti-tumor effect of MSA on cisplatin-resistant LUAD cells. Finally, We speculate that MSA in combination with autophagy inhibitors may be a promising new therapeutic strategy for the treatment of cisplatin-resistant LUAD.

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