Celecoxib induces apoptosis by the intrinsic pathway in HT‐29 colon carcinoma and A375 melanoma cells

Abstract

Chronic use of non‐steroidal anti‐inflammatory drugs (NSAIDs) reduces the incidence of cancers of the colon, skin and other organs. The risk of adverse effects associated with NSAIDs precludes the use of many of these agents in a chemoprevention strategy. We and others have demonstrated direct cytotoxic effects of the COX‐2 selective NSAID, celecoxib, in human cancer cell lines. We sought to further elucidate the cellular mechanisms involved in celecoxib's cytotoxicity in HT‐29 colon carcinoma and A375 melanoma cells. HT‐29 and A375 cells were treated for 48 hours with increasing concentrations of celecoxib followed by the XTT assay to establish an IC50 value for each cell line. The IC50 values for celecoxib were 55 μM and 60 μM in the HT‐29 and A375 cell lines respectively. Western blotting was performed to assess induction of apoptotic markers subsequent to celecoxib treatment. HT‐29 and A375 cells were treated with celecoxib at IC50 and 2× IC50 doses respectively for 24 hours. Celecoxib at the 2× IC50 doses increased expression of cleaved caspases‐3 and ‐7 and poly ADP ribose polymerase (PARP) in both HT‐29 and A375 cells. Induction of intrinsic apoptosis by celecoxib was demonstrated in both cell lines indicated by increased expression of cleaved caspase‐9. These results demonstrate that celecoxib elicits a direct cytotoxic effect via induction of the intrinsic apoptosis pathway in HT‐29 and A375 cells.