Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition. Mol Carcinog 2007 Oct;46(10):857-64
Date
04/07/2007Pubmed ID
17415779DOI
10.1002/mc.20318Scopus ID
2-s2.0-35148893494 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
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 microM, followed by sulindac sulfide (116.5 +/- 2.34 microM). 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.
Author List
Bock JM, Menon SG, Goswami PC, Sinclair LL, Bedford NS, Domann FE, Trask DKAuthor
Jonathan Bock MD Professor in the Otolaryngology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Anti-Inflammatory Agents, Non-SteroidalApoptosis
Celecoxib
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21
E2F Transcription Factors
G1 Phase
Humans
Pyrazoles
Sulfonamides
Sulindac
Tumor Cells, Cultured
