COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib

The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) wa s shown to decrease the incidence of colorectal cancer. This effect is thou ght to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) an d, subsequently, prostaglandin synthesis. However, recent studies have sugg ested that COX-independent pathways may contribute considerably to these an tiproliferative effects. To evaluate the involvement of COX-dependent and C OX-independent mechanisms further, we assessed the effects of celecoxib (se lective COX-2 inhibitor) and SC560 (selective COX-1 inhibitor) on cell surv ival, cell cycle distribution, and apoptosis in three colon cancer cell lin es, which differ in their expression of COX-2. Both drugs induced a G(0)/G( 1) phase block and reduced cell survival independent of whether or not the cells expressed COX-2. Celecoxib was more potent than SC560. The G(0)/G(1) block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin-dependent kinase-1 and an increased express ion of the cell cycle inhibitory proteins p21(Waf1) and p27(Kip1). In addit ion, celecoxib, but not SC560, induced apoptosis, which was also independen t of the COX-2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT-15 (COX-2 deficient) colon cancer xenogra fts in nude mice, but both substances had no significant effect on HT-29 tu mors, which express COX-2 constitutively. Thus, our in vitro and in vivo da ta indicate that the antitumor effects of celecoxib probably are mediated t hrough COX-2 independent mechanisms and are not restricted to COX-2 over-ex pressing tumors.