Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition. Cancer Biol Ther 2007 Jan;6(1):30-9
Date
12/19/2006Pubmed ID
17172818DOI
10.4161/cbt.6.1.3470Scopus ID
2-s2.0-33847129269 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
Sulindac sulfide and sulindac sulfone have demonstrated anti-neoplastic and chemo-preventive activity against various human tumors, but few studies have examined the relative effectiveness of these drugs against squamous cell carcinoma of the head and neck (SCCHN). These compounds are metabolites of the nonsteroidal anti-inflammatory drug sulindac and differ in their ability to inhibit cyclooxygenase-2 (COX-2) enzyme function. Sulindac sulfide (the sulindac metabolite with COX-2 inhibitory function) demonstrated strong cell growth inhibition as measured by MTT and growth assays in UM-SCC-1 and SCC-25 cells, while sulindac sulfone had only moderate effect. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G cells and activation of caspase-3. Sulindac sulfide induced expression of p21wafl/cipl in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21waf1/cip1 protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p2lwafl/ciP1 protein levels in SCCHN. Sulindac sulfide also induced dose-dependent expression of PPAR-gamma. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 microM. These results demonstrate the differential activity of sulindac metabolites and support the hypothesis that sulindac sulfide induced perturbations in SCCHN cellular proliferation could be regulated both by p21waf1/cip1-dependent cytostatic and caspase-dependent cytotoxic pathways.
Author List
Bock JM, Menon SG, Goswami PC, Sinclair LL, Bedford NS, Jackson RE, 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
ApoptosisCarcinoma, Squamous Cell
Cell Cycle
Cell Cycle Proteins
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21
Head and Neck Neoplasms
Humans
PPAR gamma
Sulindac
Tumor Suppressor Protein p53
Up-Regulation