Celecoxib Enhances the Chemotherapeutic Response of Cisplatin and TNF-α in SiHa Cells through Reactive Oxygen Species-Mediated Mitochondrial Pathway.

Recently, many studies have shown that celecoxib induces apoptosis in various cancer cells by different mechanisms depending on the cell type. This study examined the effect of the selective COX-2 inhibitor celecoxib on cisplatin and TNF-α cytotoxicity and studied the role of mitochondria in the induction of apoptosis in the human cervical carcinoma SiHa cells. Apoptosis was detected by flow cytometry. The protein expression of Bcl-2, Bcl-XL, Bax, cytochrome c and AIF was analyzed by Western Blotting. The mRNA level of anti-oxidant enzymes was quantitated by RT-PCR. Priming SiHa cells with celecoxib increased the cisplatin-induced apoptosis by 20.56% and priming with celecoxib increased the TNF-α induced apoptosis by 22.07%. This was accompanied by downregulation of Bcl-XL and Bcl-2 and upregulation of Bax. Cytosolic cytochrome c increased by 43.0% with celecoxib and TNF-α treatment but was not significant with celecoxib and cisplatin treatment. Nuclear AIF increased by 21.0% with celecoxib and cisplatin treatment whereas it was not significant with celecoxib and TNF-α treatment. The mRNA level of Mn-Superoxide dismutase, CuZn-Superoxide dismutase, Glutathione peroxidase and Catalase decreased significantly on priming with celecoxib and then treating with cisplatin or TNF-α. There was no significant increase in the activity of caspase-3 with either celecoxib or TNF-α treatment or with celecoxib and cisplatin treatment. The findings suggest that priming with celecoxib induces the TNF-α and cisplatin-mediated apoptosis in SiHa cells perhaps through ROS-mediated mitochondrial pathway.