Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells

Increased cyclooxygenase-2 (COX-2) expression in human pancreatic adenocarc inomas, as well as the growth-inhibitory effect of nonsteroidal anti-inflam matory drugs (NSAIDs) in vitro, suggests that NSAIDs may be an effective tr eatment for pancreatic cancer. Gemcitabine is currently the most effective chemotherapeutic drug available for patients with pancreatic cancer, but is only minimally effective against this aggressive disease. Clearly, other t reatment options must be identified. To design successful therapeutic strat egies involving compounds either alone or in combination with others, it is necessary to understand their mechanism of action. In the present study, w e evaluated the effects of three NSAIDs (sulindac, indomethacin, and NS-398 ) or gemcitabine in two human pancreatic carcinoma cell lines, BxPC-3 (COX- 2-positive) and PaCa-2 (COX-2-negative), previously shown to be growth-inhi bited by these NSAIDs. Effects on cell cycle and apoptosis were investigate d by flow cytometry or Western blotting. Treatment with NSAIDs or gemcitabi ne altered the cell cycle phase distribution as well as the expression of m ultiple cell cycle regulatory proteins in both cell lines, but did not indu ce substantial levels of apoptosis. Furthermore, we demonstrated that the c ombination of the NSAID sulindac or NS-398 with gemcitabine inhibited cell growth to a greater degree than either compound alone. These results indica te that the anti proliferative effects of NSAIDs and gemcitabine in pancrea tic tumor cells are primarily due to inhibition of cell cycle progression r ather than direct induction of apoptotic cell death, regardless of COX-2 ex pression. In addition, NSAIDs in combination with gemcitabine may hold prom ise in the clinic for the treatment of pancreatic cancer.