Differential activity of sulindac metabolites against squamous cell carcinoma of the head and neck is mediated by p21(waf1/cip1) induction and cell cycle inhibition

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

来源：Cancer Biology and Therapy, 2007, 6(1): 30-39.

DOI：10.4161/cbt.6.1.3470

• squamous cell carcinoma
• head and neck cancer
• sulindac
• p21(waf1/cip1)
• cell cycle

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(1) cells and activation of caspase-3. Sulindac sulfide induced expression of p21(waf1/cip1) in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21(waf1/cip1) protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p21(waf1/cip1) protein levels in SCCHN. Sulindac sulfide also induced dose dependent expression of PPAR-g. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 mu M. 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 p21(waf1/cip1)-dependent cytostatic and caspase-dependent cytotoxic pathways.

• 出版日期2007-1