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 IC(50) values were as follows: (a) aspirin, >5000 microM; (b) NO-aspirin, 1 microM; (c) sulindac, 750 microM; (d) NO-sulindac, 150 microM; (e) ibuprofen, >1000 microM; and (f) NO-ibuprofen, 42 microM. 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 G(0)-G(1) 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.
Williams
J L
JL
American Health Foundation, One Dana Road, Valhalla, NY 06595.
Borgo
S
S
Hasan
I
I
Castillo
E
E
Traganos
F
F
Rigas
B
B
D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000166:cytology / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D006131:Growth Inhibitors / Q000494:pharmacology; D019073:HT29 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D006131:Growth Inhibitors; D020030:Nitric Oxide Donors; D013467:Sulindac; D001241:Aspirin; D007052:Ibuprofen