Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alter the 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), consisting of a known nonsteroidal anti-inflammatory drug (NSAID) and a nitric oxide (NO)-releasing group, are reported safer than NSAIDs. To assess their potential in colon cancer chemoprevention, we studied in vitro the effect of NO-aspirin, NO-sulindac, and NO-ibuprofen on colonocyte kinetics. These 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 μM; (b) NO-aspirin, 1 μM; (c) sulindac, 750 μM; (d) NO-sulindac, 150 μM; (e) ibuprofen, >1000 μM; and (f) NO-ibuprofen, 42 μM. This effect was due to inhibition of proliferation and induction of apoptosis and perhaps to the induction of novel cell changes, characterized by extensive DNA degradation. NO-NSAIDs also blocked the G₀-G₁ to S cell cycle transition. Their superior effectiveness compared with traditional NSAIDs, combined with their reported safety, makes them promising candidates for chemopreventive agents against colon cancer.