INDUCTION OF APOPTOSIS IN COLON-CANCER CELLS BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Epidemiological studies have demonstrated that nonsteroidal anti-infla mmatory drugs (NSAIDs) decrease the incidence of colon cancer. In addi tion, NSAIDs reduce the number and size of polyps in patients with fam ilial adenomatous polyosis. The mechanisms of the anti-neoplastic effe ct of NSAIDs are still far from complete understanding, but one possib le mechanism is the induction of apoptosis. Several lines of evidence suggest that NSAIDs-induced apoptosis in colon cancer cells are mediat ed through the cyclooxygenase (COX)-independent pathway. In this study we explored the mechanism of NSAIDs-induced apoptosis in the colon ca ncer cell line, HT-29. We confirmed that NSAIDs induce apoptosis in HT -29 cells irrespective of their COX-selectivity. Indomethacin enhanced the expression of p21(waf-1) in HT-29 cells. However the expression o f apoptosis-related genes such as Fas, bcl-2 and bax was not affected by indomethacin. Intra-and extra-cellular calcium chelators, protein t yrosine kinase (PTK) inhibitor, protein kinase A (PKA) inhibitor and p rotein kinase C (PKC) inhibitors did not influence indomethacin-induce d apoptosis in HT-29 cells. Ne concluded that NSAIDs-induced apoptosis in colon cancer cells may be independent from signals transducted thr ough [Ca++]i, PTK, PKA, PKC or the expression of apaptosis-related gen es. In contrast, our results demonstrating the induction of p21(waf-1) transcription by NSAIDs suggest the possible association of NSAIDs-in duced apoptosis and cell-cycle control in colon cancer cells.