TY - JOUR
T1 - Proteasome inhibition enhances antitumour effects of gemcitabine in experimental pancreatic cancer
AU - Awasthi, Niranjan
AU - Schwarz, Margaret A.
AU - Schwarz, Roderich E.
PY - 2009
Y1 - 2009
N2 - Background: The clinical benefit of gemcitabine, the standard systemic therapy of pancreatic cancer (PaCa), remains modest as a result of high chemoresistance. The proteasome inhibitor bortezomib has antitumour activity against PaCa in vitro and in vivo. We examined the antitumour activity of combination PaCa therapy with bortezomib and gemcitabine. Methods: Cell proliferation assays were performed using WST-1 reagent. Protein expression was determined by Western blotting. Efficacy of bortezomib and/or gemcitabine was tested in vivo in a survival study. Results: Bortezomib at 10 μM caused 29% and 72% inhibition in AsPC-1 PaCa cell proliferation at 48 and 96 h incubation, respectively. Bortezomib was even more active against PaCa cell lines Panc-1 and MiaPaCa, with 80% inhibition of proliferation at 48 h. The combination of bortezomib and gemcitabine inhibited AsPC-1 proliferation more effectively compared with each single agent alone. Poly(ADP-ribose) polymerase (PARP) cleavage, an apoptotic indicator, reached 6.6-, 2- and 8.5-fold over controls for bortezomib, gemcitabine and the combination. The median survival was 31 (controls and bortezomib), 40 (gemcitabine) and 48 days (combination), respectively (P < 0.002). Conclusions: Bortezomib and gemcitabine demonstrate additive antitumour activity in vitro and in an experimental PaCa model, indicating the potential for clinical PaCa benefits of additional multiagent therapies that will be based upon the bortezomib and gemcitabine combination.
AB - Background: The clinical benefit of gemcitabine, the standard systemic therapy of pancreatic cancer (PaCa), remains modest as a result of high chemoresistance. The proteasome inhibitor bortezomib has antitumour activity against PaCa in vitro and in vivo. We examined the antitumour activity of combination PaCa therapy with bortezomib and gemcitabine. Methods: Cell proliferation assays were performed using WST-1 reagent. Protein expression was determined by Western blotting. Efficacy of bortezomib and/or gemcitabine was tested in vivo in a survival study. Results: Bortezomib at 10 μM caused 29% and 72% inhibition in AsPC-1 PaCa cell proliferation at 48 and 96 h incubation, respectively. Bortezomib was even more active against PaCa cell lines Panc-1 and MiaPaCa, with 80% inhibition of proliferation at 48 h. The combination of bortezomib and gemcitabine inhibited AsPC-1 proliferation more effectively compared with each single agent alone. Poly(ADP-ribose) polymerase (PARP) cleavage, an apoptotic indicator, reached 6.6-, 2- and 8.5-fold over controls for bortezomib, gemcitabine and the combination. The median survival was 31 (controls and bortezomib), 40 (gemcitabine) and 48 days (combination), respectively (P < 0.002). Conclusions: Bortezomib and gemcitabine demonstrate additive antitumour activity in vitro and in an experimental PaCa model, indicating the potential for clinical PaCa benefits of additional multiagent therapies that will be based upon the bortezomib and gemcitabine combination.
KW - Bortezomib combination therapy
KW - Experimental therapy
KW - Pancreatic cancer
KW - Proteasome inhibition
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U2 - 10.1111/j.1477-2574.2009.00109.x
DO - 10.1111/j.1477-2574.2009.00109.x
M3 - Article
C2 - 20495713
AN - SCOPUS:73349129983
SN - 1365-182X
VL - 11
SP - 600
EP - 605
JO - HPB
JF - HPB
IS - 7
ER -