Liu Siwei, Liang Bilin, Jia Huiting, Jiao Yuhan, Pang Zhongqiu, Huang Yongye
College of Life and Health Sciences Northeastern University Shenyang China.
FEBS Open Bio. 2017 Apr 27;7(6):798-810. doi: 10.1002/2211-5463.12223. eCollection 2017 Jun.
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 UC3 bladder cancer cells. Gene expression studies revealed that cotreatment with melatonin and VPA triggered the up-regulation of certain genes related to apoptosis (TNFRSF10A and TNFRSF10B), autophagy (BECN, ATG3 and ATG5) and necrosis (MLKL, PARP-1 and RIPK1). The combinatorial treatment increased the expression of endoplasmic reticulum (ER)-stress-related genes ATF6, IRE1, EDEM1 and ERdj4. Cotreatment with melatonin and VPA enhanced the expression of E-cadherin, and decreased the expression of -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 UC3 bladder cancer cells, but the clinical significance of combinatorial treatment still needs to be further exploited.
有效的药物组合有增强治疗效果和对抗耐药性的潜力。褪黑素和丙戊酸（VPA）在多种癌细胞中均表现出抗肿瘤活性。本研究旨在评估褪黑素和VPA联合抗癌作用在膀胱癌细胞中引发的细胞死亡途径。结果表明，褪黑素和VPA联合使用可显著协同抑制UC3膀胱癌细胞的生长。基因表达研究显示，褪黑素和VPA联合处理可触发与凋亡相关的某些基因（TNFRSF10A和TNFRSF10B）、自噬相关基因（BECN、ATG3和ATG5）以及坏死相关基因（MLKL、PARP - 1和RIPK1）的上调。联合处理增加了内质网（ER）应激相关基因ATF6、IRE1、EDEM1和ERdj4的表达。褪黑素和VPA联合处理增强了E - 钙黏蛋白的表达，并降低了β - 钙黏蛋白、纤连蛋白、Snail和Slug的表达。此外，联合处理激活了Wnt通路和Raf/MEK/ERK通路。然而，与单独使用褪黑素或VPA处理相比，联合处理后细胞中某些基因的表达变化未进一步增强。总之，这些发现表明，褪黑素和VPA联合处理通过调节UC3膀胱癌细胞的细胞死亡途径发挥了增强的细胞毒性作用，但联合治疗的临床意义仍有待进一步探索。
