Cyclooxygenase-2 (COX-2),involved in the inhibition of apoptosis and,the potentiation of cell growth,is frequently overexpressed in human malignancies including osteosarcoma (OS).We have attempted to identify the anti-proliferation of celecoxib,a selective COX-2 inhibitor,and the combination of celecoxib and cisplatin in MG-63 cells,and to explore the potential molecular mechanisms involved.MG-63 cells were treated with the combination of celecoxib and cisplatin or either agent alone for 48 h in serum-supplemented medium.Celecoxib caused G1 phase arrest and significantly inhibited cell growth,as well as potentiating cisplatin-induced apoptosis.The effect was dose-dependent,and apoptotic changes such as DNA fragments and apoptotic bodies were observed.However,downregulation of COX-2 did not occur in cells treated with celecoxib.Phosphoinositide-3-kinase (PI3K)/Akt,survivin,bcl-2 were significantly downregulated in cells treated with the combination of celecoxib and cisplatin,and decreased survivin and bcl-2 levels were found in cells with wortmarmin,a specific PI3K inhibitor.Moreover,the decreased expressions of procaspase-9,procaspase-3 and cleaved PARP-1 were detected by Westem blot analysis.Therefore,celecoxib exerts its anti-tumor activities through COX-2-independent mechanisms,which may be PI3K/Akt-dependent,and survivin and bcl-2-related.PI3K may be at the center of the celecoxib effects,which play an essential role in the regulation of survivin and Bcl-2.