富马酸二甲酯通过GSH耗竭/ ROS增加/ MAPKs活化途径诱导结肠癌细胞坏死。,British Journal of Pharmacology

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富马酸二甲酯通过GSH耗竭/ ROS增加/ MAPKs活化途径诱导结肠癌细胞坏死。
British Journal of Pharmacology ( IF 6.8 ) Pub Date : 2015-05-09 , DOI: 10.1111/bph.13184
Xin Xie ₁ , Yu Zhao ₁ , Chun-Yan Ma ₁ , Xiao-Ming Xu ₁ , Yan-Qiu Zhang ₁ , Chen-Guang Wang ₁ , Jing Jin ₁ , Xin Shen ₁ , Jin-Lai Gao ₁ , Na Li ₁ , Zhi-Jie Sun ₂ , De-Li Dong ₁

Affiliation

背景与目的富马酸二甲酯（DMF）是一种新批准的药物，用于治疗复发型多发性硬化症和复发缓解型多发性硬化症。在这里，我们研究了DMF及其代谢物富马酸单甲酯（MMF和甲醇）对不同胃肠道癌细胞系的影响以及涉及的潜在分子机制。实验方法通过MTT或CCK8测定法测量细胞活力。通过蛋白质印迹分析测量蛋白质表达。使用商业试剂盒检查了LDH释放，活细胞和死细胞染色，细胞内GSH水平以及线粒体膜电位。关键结果正如药理学工具necrostatin-1，透射电镜，LDH和HMGB1在CT26细胞中的释放所证实的，DMF而非MMF诱导的细胞坏死。通过与GSH和N-乙酰半胱氨酸（NAC）共同处理CT26细胞，可以抑制DMF诱导的细胞GSH水平降低以及细胞活力和活性氧（ROS）升高。DMF激活CT26细胞中的JNK，p38和ERK MAPK，JNK，p38和ERK抑制剂部分逆转了DMF诱导的细胞活力下降。GSH或NAC处理抑制了CT26细胞中DMF诱导的JNK，p38和ERK活化。DMF而不是MMF会增加SGC-7901，HCT116，HT29和CT26癌细胞中的自噬反应，但自噬抑制作用并不能阻止DMF诱导的细胞活力下降。结论和意义DMF而不是其代谢产物MMF通过涉及GSH耗竭，ROS升高和MAPK激活的机制诱导结肠癌细胞坏死。

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Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway.

BACKGROUND AND PURPOSE Dimethyl fumarate (DMF) is a newly approved drug for the treatment of relapsing forms of multiple sclerosis and relapsing-remitting multiple sclerosis. Here, we investigated the effects of DMF and its metabolites mono-methylfumarate (MMF and methanol) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms involved. EXPERIMENTAL APPROACH Cell viability was measured by the MTT or CCK8 assay. Protein expressions were measured by Western blot analysis. LDH release, live- and dead-cell staining, intracellular GSH levels, and mitochondrial membrane potential were examined by using commercial kits. KEY RESULTS DMF but not MMF induced cell necroptosis, as demonstrated by the pharmacological tool necrostatin-1, transmission electron microscopy, LDH and HMGB1 release in CT26 cells. The DMF-induced decrease in cellular GSH levels as well as cell viability and increase in reactive oxygen species (ROS) were inhibited by co-treatment with GSH and N-acetylcysteine (NAC) in CT26 cells. DMF activated JNK, p38 and ERK MAPKs in CT26 cells and JNK, p38 and ERK inhibitors partially reversed the DMF-induced decrease in cell viability. GSH or NAC treatment inhibited DMF-induced JNK, p38, and ERK activation in CT26 cells. DMF but not MMF increased autophagy responses in SGC-7901, HCT116, HT29 and CT26 cancer cells, but autophagy inhibition did not prevent the DMF-induced decrease in cell viability. CONCLUSION AND IMPLICATIONS DMF but not its metabolite MMF induced necroptosis in colon cancer cells through a mechanism involving the depletion of GSH, an increase in ROS and activation of MAPKs.

更新日期：2019-11-01

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