The celecoxib concentrations are 4 to 11 fold greater than 8M,the human plasma concentration of celecoxib after consumption of 800 mg kg per day and the concentration that is presently used in this study. Mazzanti et al. Paclitaxel recently showed that celecoxib induces apoptosis,but lower concentrations Inhibitors,Modulators,Libraries of celecoxib induce autophagy in hepatocellular carcinoma cells that are cultured 17-DMAG fda in serum free medium. The sensitivity of tumour cells to celecoxib induced cellular apoptosis or autophagy is likely to be concentration Inhibitors,Modulators,Libraries or tumour type dependent. The role of p53 in autophagy remains contro versial with studies suggesting activation of p53,as well as inhibition of p53,as inductive of autophagy.

In our study,induction of autophagy by celecoxib in glioblast oma cells is p53 dependent,as shown by the autophagy induction only Inhibitors,Modulators,Libraries in celecoxib treated glioblastoma cells with high functional level of p53.

In con trast,Mazzanti et al. reported Inhibitors,Modulators,Libraries that induction of autophagy by celecoxib is mediated by P glycoprotein and Bcl2 via a p53 independent mechanism. The role of autophagy in cancer development is complex,as it has been implicated in both tumour survival and tumour cell death. Induction of cell cycle arrest pre ceding autophagy induction inhibits tumor growth. Inhibitors,Modulators,Libraries Our results support the induction of p53 dependent G1 cell cycle arrest,followed by autophagy as a mechanism for celecoxib to prevent glioma cell survival. Induction of p53 dependent autophagy independent of apoptosis should be considered as one of the underlying anti prolif erative mechanisms of COX 2 inhibitors,celecoxib in par ticular,in various tumours.

We investigated the up stream mechanisms preceding p53 activation in Inhibitors,Modulators,Libraries U87MG cells treated with celecoxib. We found that celecoxib induced DNA dam age,accompanied with inhibition of DNA synthesis in U87MG cells,which led to p53 induced G1 cell cycle arrest and autophagy events. These findings of celecoxib induced Inhibitors,Modulators,Libraries DNA damage followed by p53 dependent G1 cell cycle arrest and autophagy are clinically relevant since low concentration of celecoxib are attainable in human serum. In cancer cells,DNA damage was induced following celecoxib treatment in murine lung Inhibitors,Modulators,Libraries and mammary cancer cells,and by the non selective COX inhibitor aspirin in HT 29 human colon carcinoma.

Activation of DNA damage p53 signal ling by COX 2 inhibitors has not been reported.

One study proposes induction of DNA damage by the COX inhibitor R flurbiprofen following the observation that R flurbiprofen increases p53 phosphorylation in colon Inhibitors,Modulators,Libraries cancer cells,but this has yet to be verified. Inhibitors,Modulators,Libraries Our study demonstrates that selective COX 2 inhibition by celecoxib induces DNA damage and inhibits DNA synthe sis,resulting in p53 activation and http://www.selleckchem.com/products/epz-5676.html subsequent anti prolif erative effects in glioblastoma cells. The mechanisms underlying currently celecoxib induced DNA damage remain unclear and are beyond the scope of this study.