TY - JOUR
T1 - Celecoxib synergizes human pancreatic ductal adenocarcinoma cells to sorafenib-induced growth inhibition.
AU - Rosendahl, Ann
AU - Gundewar, Chinmay
AU - Said Hilmersson, Katarzyna
AU - Karnevi, Emelie
AU - Andersson, Roland
PY - 2012
Y1 - 2012
N2 - 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.
CONCLUSION:
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
AB - 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.
CONCLUSION:
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
U2 - 10.1016/j.pan.2012.04.005
DO - 10.1016/j.pan.2012.04.005
M3 - Article
C2 - 22687377
SN - 1424-3903
VL - 12
SP - 219
EP - 226
JO - Pancreatology
JF - Pancreatology
IS - 3
ER -