Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alterthe kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: Implications for colon cancer chemoprevention

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs), co nsisting of a known nonsteroidal anti-inflammatory drug (NSAID) and a nitri c oxide (NO)-releasing group, are reported safer than NSAIDs. To assess the ir potential in colon cancer chemoprevention, we studied in vitro the effec t of NO-aspirin, NO-sulindac, and NO-ibuprofen on colonocyte kinetics. Thes e three NO-NSAIDs reduced the growth of cultured HT-29 colon adenocarcinoma cells much more effectively than the corresponding NSAIDs; e.g., at 24 h, their IC50 values were as follows: (a) aspirin, >5000 muM; (b) NO-aspirin, 1 muM; (c) sulindac, 750 muM; (d) NO-sulindac, 150 muM; (e) ibuprofen, >100 0 muM; and (f) NO-ibuprofen, 42 muM This effect was due to inhibition of pr oliferation and induction of apoptosis and perhaps to the induction of nove l cell changes, characterized by extensive DNA degradation. NO-NSAIDs also blocked the G(0)-G(1) to S cell cycle transition. Their superior effectiven ess compared with traditional NSAIDs, combined with their reported safety, makes them promising candidates for chemopreventive agents against colon ca ncer.