Document Detail


Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition.
MedLine Citation:
PMID:  17172818     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jonathan M Bock; Sarita G Menon; Prabhat C Goswami; Lori L Sinclair; Nichole S Bedford; Robert E Jackson; Douglas K Trask
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Cancer biology & therapy     Volume:  6     ISSN:  1538-4047     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-07-04     Completed Date:  2007-08-09     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  30-9     Citation Subset:  IM    
Affiliation:
Department of Otoloryngology, Head and Neck Surgery, University of Iowa Health Care, Iowa City, Iowa 52242, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis
Carcinoma, Squamous Cell / metabolism*
Cell Cycle / drug effects
Cell Cycle Proteins / metabolism
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Head and Neck Neoplasms / metabolism*
Humans
PPAR gamma / antagonists & inhibitors
Sulindac / analogs & derivatives*,  metabolism,  pharmacology
Tumor Suppressor Protein p53 / metabolism
Up-Regulation
Grant Support
ID/Acronym/Agency:
SK08 CA104631/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/PPAR gamma; 0/Tumor Suppressor Protein p53; 32004-67-4/sulindac sulfide; 38194-50-2/Sulindac; 59864-04-9/sulindac sulfone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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