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Non‐steroidal anti‐inflammatory drugs (NSAIDs) inhibit IEC‐6 cell migration and calpain protein expression.
Author(s) -
Lillich James D,
Silver K,
Raveendran N,
Freeman L
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a808-c
Subject(s) - calpain , calpastatin , proteases , pharmacology , chemistry , western blot , cell , toxicity , caco 2 , blot , biochemistry , gene , medicine , enzyme , organic chemistry
Chronic treatment with non‐steroidal anti‐inflammatory drugs (NSAIDs) inhibits intestinal epithelial cell migration (IEC‐6). Microarray analysis was used to generate novel hypotheses about mechanisms that contribute to gastrointestinal NSAID toxicity. IEC‐6 monolayers were treated with ulcerogenic NSAIDs, indomethacin and NS‐398, and the non‐ulcerogenic SC‐560. Bio‐informatic analysis revealed that ulcerogenic NSAIDs either decreased the gene expression of cysteine proteases (calpains) or increased the gene expression of the endogenous inhibitor of calpains, calpastatin. The role calpains play in cell migration via focal adhesion turnover caused us to hypothesize that NSAID‐altered expression of calpain genes and protein could contribute to drug toxicity. Accordingly, treatment with calpain 1 and 2 inhibitors (ALLM and ALLN; 4 hrs), and ulcerogenic NSAIDs (72 hrs) retarded the migration of IEC‐6 monolayers in response to physical wounded. Western blot analysis was performed on whole cell lysates from NSAID treated IEC‐6 monolayers. Ulcerogenic NSAIDs decreased protein expression of calpain 1 and 2, but not calpastatin. These results suggest that calpains are vital to IEC‐6 cell migration and provide the first evidence that NSAIDs toxicity is mediated in part by drug effects on calpain activity. (Support: NIH P20‐ RR017686 )