Celecoxib synergizes human pancreatic ductal adenocarcinoma cells to sorafenib-induced growth inhibition.
BACKGROUND
Pancreatic ductal adenocarcinoma is frequently associated with aberrant activation of the Ras/Raf/MAPK pathway and cyclooxygenase-2 (COX-2) overexpression. This study evaluated the potential for combining the multikinase inhibitor sorafenib and the specific COX-2 inhibitor celecoxib as therapy in pancreatic ductal adenocarcinoma cells.


METHODS
BxPC-3, MIAPaCa-2, PANC-1 and AsPC-1 pancreatic adenocarcinoma cells were exposed to sorafenib and celecoxib combined treatment in vitro. 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 synergistically inhibited pancreatic adenocarcinoma cell proliferation. This regimen produced combination index (CI) values between 0.67 and 0.92 for the various cell lines, indicating significant synergistic interactions between sorafenib and celecoxib, which also markedly inhibited the migratory capacity. The growth inhibition was associated with an accumulation of cells in the G(0)/G(1) phase of the cell cycle and induction of apoptosis. These changes were accompanied by a significant reduction of p21(WAF1/Cip1) levels, where celecoxib sensitized the cells to sorafenib-mediated p21(WAF1/Cip1) suppression.


CONCLUSIONS
These results suggest that combined treatment with sorafenib and celecoxib synergistically induce growth inhibition and apoptosis in pancreatic adenocarcinoma cells through a process involving p21(WAF1/Cip1) suppression.
Department of Surgery, Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.
Ann H
AH
Rosendahl
Chinmay
C
Gundewar
Katarzyna
K
Said
Emelie
E
Karnevi
Roland
R
Andersson
D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage*
D001557:Benzenesulfonates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D052246:Cyclooxygenase 2 Inhibitors; D010671:Phenylurea Compounds; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D009536:Niacinamide; D000077157:Sorafenib; D000068579:Celecoxib