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Tumor Biology |
Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, Division of Experimental Medicine (R. J. L.) and Department of Medicine and Oncology (M. P.), McGill University, Montreal, Quebec, Canada, H3T 1E2
Cyclooxygenase (COX)-2 inhibitors demonstrate modest antineoplastic activity in experimental models of human malignancies, but little is known about factors that may confer resistance to their antiproliferative actions. We observed that fetal bovine serum antagonizes growth inhibition and G1 arrest induced by two COX-2 inhibitors (NS-398 and celecoxib) on BxPC-3 pancreatic cancer cells. We investigated the hypothesis that insulin-like growth factor I (IGF-I), a major survival factor present in serum, mediates these effects. Treatment of BxPC-3 cells with 25 µM celecoxib in 1% fetal bovine serum-containing medium for 48 h resulted in a 
40% decrease in cell viability. Coincubation of BxPC-3 cells with 25 µM celecoxib and 50 ng/ml IGF-I resulted in complete attenuation of the celecoxib-associated decrease in cell viability. Cell cycle analysis revealed that this IGF-I-induced increase in cell viability was correlated with an IGF-I-induced inhibition of celecoxib-mediated G1 arrest. Similar results were observed when another COX-2 inhibitor (50 µM NS-398) was used. When IGF-binding protein-3 (an inhibitor of IGF-I bioactivity) was added in combination with 25 µM celecoxib, enhanced growth inhibition was observed (60% decrease in cell viability). Treatment of BxPC-3 cells with a higher dose (50 µM) of celecoxib for 24 h resulted in the induction of apoptosis, as assayed by flow cytometry and poly(ADP-ribose) polymerase cleavage. Addition of 50 ng/ml IGF-I resulted in a complete attenuation of celecoxib-induced apoptosis. The protection from celecoxib-induced apoptosis by IGF-I correlated with an increase in the levels of the activated antiapoptotic protein Akt. These results suggest that alterations of IGF-I levels or IGF-I receptor signal transduction modulate the antineoplastic actions of COX-2 inhibitors.
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