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Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ ROS increase/ MAPKs activation pathway
Author(s) -
Xie Xin,
Zhao Yu,
Ma ChunYan,
Xu XiaoMing,
Zhang YanQiu,
Wang ChenGuang,
Jin Jing,
Shen Xin,
Gao JinLai,
Li Na,
Sun ZhiJie,
Dong DeLi
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13184
Subject(s) - viability assay , necroptosis , chemistry , p38 mitogen activated protein kinases , dimethyl fumarate , mapk/erk pathway , reactive oxygen species , cancer cell , glutathione , programmed cell death , autophagy , intracellular , cell growth , mtt assay , microbiology and biotechnology , cell , biochemistry , apoptosis , kinase , biology , cancer , immunology , genetics , multiple sclerosis , enzyme
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 CCK 8 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 HMGB 1 release in CT 26 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 CT 26 cells. DMF activated JNK , p38 and ERK MAPKs in CT 26 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 CT 26 cells. DMF but not MMF increased autophagy responses in SGC ‐7901, HC T116, HT 29 and CT 26 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 .