title: Insulin-like growth factor-I antagonizes the antiproliferative effects of cyclooxygenase-2 inhibitors on BxPC-3 pancreatic cancer cells.
abstract: 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 G(1) 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 micro M celecoxib in 1% fetal bovine serum-containing medium for 48 h resulted in a approximately 40% decrease in cell viability. Coincubation of BxPC-3 cells with 25 micro M 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 G(1) arrest. Similar results were observed when another COX-2 inhibitor (50 micro M NS-398) was used. When IGF-binding protein-3 (an inhibitor of IGF-I bioactivity) was added in combination with 25 micro M celecoxib, enhanced growth inhibition was observed (approximately 60% decrease in cell viability). Treatment of BxPC-3 cells with a higher dose (50 micro M) 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.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada, H3T 1E2.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Levitt
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
mesh_terms: D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018972:Insulin-Like Growth Factor Binding Protein 3; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007334:Insulin-Like Growth Factor I; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib