Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition

Jonathan M Bock; Sarita G Menon; Prabhat C Goswami; Lori L Sinclair; Nichole S Bedford; Robert E Jackson; Douglas K Trask

doi:10.4161/cbt.6.1.3470

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Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition

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Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition

Jonathan M Bock, Sarita G Menon, Prabhat C Goswami, Lori L Sinclair, Nichole S Bedford, Robert E Jackson and Douglas K Trask

Cancer biology & therapy, Vol.6(1), pp.30-39

01/2007

DOI: 10.4161/cbt.6.1.3470

PMID: 17172818

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Abstract

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.

Apoptosis

Up-Regulation

Carcinoma, Squamous Cell - metabolism

Humans

Cell Cycle Proteins - metabolism

Tumor Suppressor Protein p53 - metabolism

Head and Neck Neoplasms - metabolism

Sulindac - metabolism

Sulindac - analogs & derivatives

PPAR gamma - antagonists & inhibitors

Cyclin-Dependent Kinase Inhibitor p21 - metabolism

Cell Proliferation - drug effects

Cell Cycle - drug effects

Sulindac - pharmacology

Details

Title: Subtitle: Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21waf1/cip1 induction and cell cycle inhibition
Creators: Jonathan M Bock - Department of Otoloryngology, Head and Neck Surgery, University of Iowa Health Care, Iowa City, Iowa 52242, USA
Sarita G Menon
Prabhat C Goswami
Lori L Sinclair
Nichole S Bedford
Robert E Jackson
Douglas K Trask
Resource Type: Journal article
Publication Details: Cancer biology & therapy, Vol.6(1), pp.30-39
DOI: 10.4161/cbt.6.1.3470
PMID: 17172818
NLM abbreviation: Cancer Biol Ther
ISSN: 1538-4047
eISSN: 1555-8576
Publisher: United States
Grant note: SK08 CA104631 / NCI NIH HHS
Language: English
Date published: 01/2007
Academic Unit: Radiation Oncology
Record Identifier: 9984046929902771

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