In:
British Journal of Pharmacology, Wiley, Vol. 172, No. 15 ( 2015-08), p. 3929-3943
Abstract:
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 .
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1111/bph.2015.172.issue-15
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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