Celecoxib activates apoptotic proteins

Celecoxib activates apoptotic proteins more BAD,caspases and PARP,followed by cell apoptosis and reduced tumour cell proliferation. Anti tumour selleck chem inhibitor mechanisms of COX 2 inhibitors also Inhibitors,Modulators,Libraries include inhibition of tumour angiogenesis,inhi bition of prostaglandin induced immunosuppressive activity and increased DNA damage reduced DNA repair capacity. Peroxidation of arachidonic acid into prostaglandins by COX generates reactive oxygen species and free radicals,which induce DNA damage and tumour igenicity. Inhibition Inhibitors,Modulators,Libraries of COX by COX inhibitors aspi rin,nimesulide,rofecoxib and celecoxib protects DNA from oxidative damage by scavenging hydroxyl radicals and superoxide in vitro in non tumour models. However,prevention of DNA damage by COX inhibitors has not been reported in tumour cells.

Inhibitors,Modulators,Libraries In con trast,aspirin significantly induces DNA damage of HT 29 human colon carcinoma,whereas Inhibitors,Modulators,Libraries celecoxib causes DNA damage in MCa 35 murine mammary and A549 human lung cancer cells. Whether COX 2 inhibitors induce DNA damage in glioblastoma cells is unclear. Mutational inactivation of the tumour suppressor gene p53 is frequently found in human tumours,with p53 mutation inactiva tion reported in 63 65% of high grade gliomas. Induction of DNA damage initiates a cascade of signalling with p53 activation and subsequent transcriptional activation of p53 response genes,thus provoking cell cycle arrest and or apoptosis. Genotoxic stress caused by DNA damag ing agents also induce p53 dependent autophagy,the type II programmed cell death characterised by the for mation of cytosolic double membrane vesicles that engulf cellular content by diges tion,when fused with lysosomes.

The mechanisms of p53 dependent induction of autophagy are not fully understood,but are thought to involve both the transcrip tion independent Inhibitors,Modulators,Libraries functions Inhibitors,Modulators,Libraries and transcription dependent functions. Anti tumour mechanisms by COX inhibition have been shown to be either p53 dependent Inhibitors,Modulators,Libraries or p53 independent Inhibitors,Modulators,Libraries in various cancer and non cancer cells. The anti proliferative mechanism of COX 2 inhibitors underpin by autophagy induction in tumours is unclear. Inhibitors,Modulators,Libraries To date,only one recent report suggests that celecoxib Inhibitors,Modulators,Libraries induces both autophagy and apoptosis,medi ated by P glycoprotein independent of p53 mechanisms,in hepatocellular carcinoma cells.

The role of p53 in celecoxib induced autophagy and celecoxib find more information induced anti proliferative responses clearly needs to be verified.

In this study,we investigated whether the anti prolif erative response induced CT99021 by celecoxib was dependent on the presence of functional p53 and b whether celecoxib induced DNA damage resulted in p53 dependent G1 cell cycle arrest,followed by apoptosis or autophagy. We stud ied the effect of celecoxib in human glioblastoma cells with various p53 status,U87MG cells with high and low levels of p53,LN229 and U373MG cells.

Celecoxib activates apoptotic proteins