The anti-apoptotic property of NS-398 at high dose can be mediated in part through NF-kappaB activation, hsp70 induction and a decrease in caspase-3 activity in human osteosarcoma cells.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to produce an anti-proliferative and pro-apoptotic effect on different types of cancer cell lines. Previously, we demonstrated that high dose of NS-398 (100 microM), a selective cyclooxygenase-2 inhibitor, induced a cell cycle slowing or arrest and, in contrast to low dose (10 microM), a marked decrease in apoptosis in human 1547 osteosarcoma cells. In this study, we investigated particularly the effect of 100 microM NS-398 on p53 and p21 expression, caspase activities and nuclear factor-kappaB (NF-kappaB). We found a correlation between p53, p21 mRNA expression and NF-kappaB activation and, we observed an induction of heat shock protein 70 expression with a large decrease in caspase-3 activity after 100 microM NS-398 treatment. Moreover, the inhibition of apoptosis was correlated with an increase in bcl-2/bax ratio. Our new findings confirm the novel anti-apoptotic property of NS-398 at 100 microM, as we previously found, which contrasts to the described NS-398 pro-apoptotic effect on other cancer cell lines.
Moalic-Juge
Sandra
S
Laboratoire de Biochimie, UPRES EA 1085, Faculté de Pharmacie, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Liagre
Bertrand
B
Duval
Raphaël
R
Corbiere
Cecile
C
Bianchi
Arnaud
A
Bordji
Karim
K
Bosgiraud
Claudine
C
Beneytout
Jean-Louis
JL
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016158:Genes, p53; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology*; D012516:Osteosarcoma / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016861:Cyclooxygenase Inhibitors; D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; D018808:Transcription Factor AP-1; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases