Abstract 4459: Apricoxib upregulates 15-PGDH and PGT in HNSCC

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Head and neck squamous cell carcinoma (HNSCC), is the sixth most common cancer in the world. Patients with HNSCC are at considerable risk of mortality, with more than 300,000 deaths attributable to the disease per year. The five-year survival rate for patients with advanced head and neck cancer remains approximately 15-20 percent, emphasizing the importance of new therapeutic strategies. In spite of extensive research on EGFR and COX-2 inhibitors, their combined use for HNSCC is still in its developmental stage. We evaluated the efficacy of the newer COX-2 inhibitor, apricoxib, in HNSCC cell lines. Here, we report that in comparison with celecoxib, apricoxib shows greater efficacy in vitro; and we define the mechanisms which may be responsible for this. Our studies show that apricoxib is effective in preventing tumor cell growth in 3-dimensional, and anchorage-independent growth assays; as well as decreasing the capacity for tumor cell migration. Treatment of HNSCC cells with apricoxib also causes greater up regulation of E-cadherin expression and down regulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to EGFR TKI. In addition to PGE2 down regulation, indicating COX-2 inhibition, we also show that apricoxib treatment causes a marked up regulation of 15-PGDH (prostaglandin dehydrogenase) and PGT (prostaglandin transporter), both of which decrease PGE2. These effects are further amplified in 3-dimensional culture, indicating the import of the microenvironment in drug efficacy. This up regulation of 15-PGDH and PGT with apricoxib treatment may explain its increased efficacy over celecoxib in the assays we tested. As apricoxib affects other pathways of PGE2 degradation and uptake, there is ultimately less PGE2 to drive metastasis and tumor progression. These newly defined mechanisms for the increased efficacy of apricoxib have important implications for targeted chemoprevention and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4459.