Abstract LB-226: Celecoxib synergizes human pancreatic ductal adenocarcinoma cells to sorafenib-induced growth inhibition involving p21 suppression

Abstract

Abstract Purpose: The aim of this study was to evaluate the potential for combining the multikinase inhibitor sorafenib and the specific cyclo-oxygenase 2 (COX-2) inhibitor celecoxib as therapy in pancreatic adenocarcinoma cells and to test the hypothesis that a synergistic or additive effect on the Ras/MAPK/ERK and related pathways might be obtained. Experimental design: COX-2 positive (BxPC-1) and low/negative (MIAPaCa-2, PANC-1 and AsPC-1) human pancreatic adenocarcinoma cells were exposed to sorafenib and celecoxib combined treatment in vitro, after which cell viability and various growth promoting and survival signaling pathways were monitored by MTT, flow cytometry and Western blotting. Results: Combined treatment with sorafenib and celecoxib resulted in synergistic inhibition of pancreatic adenocarcinoma cell proliferation through COX-2 independent mechanisms. This regimen produced combination index (CI) values between 0.67 and 0.92 for the various cell lines, suggesting significant synergistic interactions between sorafenib and celecoxib, which also markedly inhibited the migratory capacity. The growth inhibition was associated with a reduction of basal ERK1/2 activity, accumulation of cells in the G0/G1 phase of the cell cycle, induction of apoptosis and poly(ADP-ribose) polymerase cleavage. These changes were accompanied by a significant reduction of p21WAF1/Cip1 levels, where celecoxib sensitized the cells to sorafenib-mediated p21WAF1/Cip1 suppression. Conclusion: p21WAF1/Cip1 levels are elevated frequently in human pancreatic adenocarcinoma and increases with disease progression. In this study we demonstrate that combined treatment with sorafenib and celecoxib synergistically induce growth inhibition and apoptosis through a process involving phospho-ERK1/2 and p21WAF1/Cip1 suppression. These data suggest the combined treatment of sorafenib and celecoxib as potential therapy for clinical testing in patients with pancreatic adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-226. doi:10.1158/1538-7445.AM2011-LB-226