sulindac-sulfone and Head-and-Neck-Neoplasms

The most common neoplasm arising in the upper gastrointestinal tract is head and neck squamous cell carcinoma (HNSCC). This is an aggressive epithelial malignancy. Many growth factors and cytokines have been discovered that are responsible for the growth and formation of tumours. Among these factors, beta-catenin is considered to be the most important for reducing cell-cell adhesions in malignant tissue. The degradation of beta-catenin triggers apoptosis by different routes. Sulindac sulfone has been shown to induce apoptosis in several different tumours. In the present study, we surveyed the concentration of beta-catenin in an HNSCC line after incubation with different concentrations of sulindac sulfone.. Immunohistochemical and Western blot analyses were performed after treatment of the UMSCC 11A cell line with different concentrations of sulindac sulfone (100, 200, 400, 600 and 800 microMol) for 48 hours.. At 100 microMol of sulindac sulfone, a decrease in beta-catenin concentration of 5% was observed; increasing concentrations of sulindac sulfone resulted in >70% reduction in secreted beta-catenin. Thus in conclusion, incubation with sulindac sulfone seemed to stop proliferation. With respect to the controls, there was no greater reduction in total protein.. In this study, sulindac sulfone reduced levels of secreted beta-catenin in the HNSCC cell line UM-SCC 11A after 48 hours of incubation. It is presumed that reduction of cell-cell adhesion, which is predominately affected by beta-catenin, is an essential step in the progression from localized malignancy to stromal and vascular invasion and ultimately metastatic disease. The reduction in the level of mural expression of beta-catenin has been associated with loss of differentiation in laryngeal carcinomas. Thus, prevention of intracellular beta-catenin accumulation is regarded as an attractive target for chemopreventive agents.

Topics: Antineoplastic Agents; beta Catenin; Blotting, Western; Carcinoma, Squamous Cell; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Sulindac; Tumor Cells, Cultured

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.

Topics: Apoptosis; Carcinoma, 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

Approximately 310,000 new cases of oral and pharynx cancer account for a major cause of neoplasm related morbidity and mortality world-wide. Unfortunately, the survival rate has not improved significantly in the last decade. The vast majority of head and neck cancer is squamous cell carcinoma. The major adhesion-proteins involved in the development and maintenance of all solid tissue are the Cadherins. Cadherins are the transmembrane components of the adherent junction with interaction with plakoglobin and beta-catenin. Downregulation of Cadherins and catenins is frequently observed in many types of human cancer. Sulindac sulfone is one of the new therapeutic apoptotic agents that show promise in the treatment of cancer. In this study, we incubated sulindac sulfone with a head and neck cancer cell line and investigated the outcome of E-Cadherin. Immunohistochemical and Western blot analyses were then performed, with different concentrations of sulindac sulfone (100, 200, 400, 600, and 800 microMol) for 48 h. At 400 microMol of sulindac sulfone a decrease of 21% was observed; at 600 microMol, 44% decrease of beta-catenin concentration was seen, and incubation with 800 microMol resulted in 73% reduction of secreted beta-catenin. Incubation with sulindac sulfone seemed to stop proliferation; however, with respect to the controls, there was no increased reduction of the total protein. Sulindac sulfone resulted in an increase of E-Cadherin content in the head and neck squamous cell cancer cell line after 48 h of incubation; however, the reactivity was restricted to the adherent junctions. At increasing concentrations of sulindac sulfone, intercellular E-Cadherin immunostaining intensifyied. ELISA also depicted significant rising levels of E-Cadherin. Sulindac sulfone contributes to the inactivation of cGMP phospho-diesterase. Thus, the accumulation of cellular cGMP and protein kinase G is induced. The following degradation of the phosphorylated beta-catenin and the dissociation from the Cadherin-catenin complex releases E-Cadherin. This may also contribute to growth inhibition and co-ordinate with apoptosis induction. It is not really clear as to, which pathway results in the elevation of the E-Cadherin proteins. However, in epithelial cancer cells, the Cadherin-catenin complex serves as a target for the chemopreventive agent, sulindac sulfone.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antineoplastic Agents; Apoptosis; beta Catenin; Cadherins; Carcinoma, Squamous Cell; Cell Adhesion; Cyclic GMP; Head and Neck Neoplasms; Humans; Immunohistochemistry; Protein Kinase C; Sulindac; Tumor Cells, Cultured; Up-Regulation