Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition.
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.
Bock
Jonathan M
JM
Department of Otoloryngology, Head and Neck Surgery, University of Iowa Health Care, Iowa City, Iowa 52242, USA.
Menon
Sarita G
SG
Goswami
Prabhat C
PC
Sinclair
Lori L
LL
Bedford
Nichole S
NS
Jackson
Robert E
RE
Trask
Douglas K
DK
D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D013467:Sulindac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047495:PPAR gamma; D016159:Tumor Suppressor Protein p53; D013467:Sulindac; C025462:sulindac sulfide; C025463:sulindac sulfone