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Relative non‐steroidal anti‐inflammatory drug (NSAID) antiproliferative activity is mediated through p21‐induced G1 arrest and E2F inhibition
Author(s) -
Bock Jonathan M.,
Me Sarita G.,
Goswami Prabhat C.,
Sinclair Lori L.,
Bedford Nichole S.,
Domann Frederick E.,
Trask Douglas K.
Publication year - 2007
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20318
Subject(s) - celecoxib , sulindac , pharmacology , rofecoxib , piroxicam , flurbiprofen , ibuprofen , naproxen , chemistry , mechanism of action , apoptosis , biology , cyclooxygenase , medicine , biochemistry , in vitro , enzyme , alternative medicine , pathology , nonsteroidal
This study was performed to compare the relative antineoplastic activity of 10 different non‐steroidal anti‐inflammatory drugs (NSAIDs) in clinical use, and to investigate the underlying mechanisms of this activity in a squamous cell carcinoma of the head and neck model (SCCHN). A standard 5‐day MTT assay was used to calculate IC 50 values in UM‐SCC‐1 cells for 10 NSAIDs, including celecoxib, rofecoxib, sulindac sulfide, sulindac sulfone, indomethacin, ketoprofen, flurbiprofen, naproxen, piroxicam, and aspirin. Celecoxib, a COX‐2 specific inhibitor, was by far the most potent NSAID, with an IC 50 of 39.9 ± 1.1 µM, followed by sulindac sulfide (116.5 ± 2.34 µM). Celecoxib and sulindac sulfide also induced more activation of caspase‐3 than any other NSAID. Cell cycle analysis showed that celecoxib and sulindac sulfide both induced a 3‐fold increase in G 1 phase distribution, and this correlated with strong induction of p21 waf1/cip1 , inhibition of cyclin D1, and hypophosphorylation of Rb. Celecoxib and sulindac sulfide treatment induced strong downstream inhibition of E2F transactivating activity as determined by a luciferase reporter assay. These data demonstrate the wide range of activity of various NSAID agents, and reveal a mechanism of action through cell cycle inhibition and induction of apoptosis. © 2007 Wiley‐Liss, Inc.