NONSTEROIDAL ANTIINFLAMMATORY DRUGS INHIBIT THE PROLIFERATION OF COLON ADENOCARCINOMA CELLS - EFFECTS ON CELL-CYCLE AND APOPTOSIS

Aspirin and other NSAIDs reduce the incidence of and mortality from co lon cancer, but their mechanism of action remains unknown. We evaluate d the effect of aspirin (ASA) and three other structurally unrelated N SAIDs (indomethacin, naproxen, and piroxicam) on cell proliferation, c ell cycle phase distribution, and the development of apoptosis in HT-2 9 colon adenocarcinoma cells in vitro. All of the NSAIDs examined redu ced the proliferation and altered the morphology of these cells in a t ime- and concentration-dependent manner. In addition, they altered the cell cycle phase distribution of these cells. They increased the prop ortion of cells in the G(0)/G(1) phase and reduced the proportion in t he S phase of the cell cycle. ASA and indomethacin also reduced the pe rcentage of cells in the G(2)/M phase, whereas naproxen and piroxicam did not. Parallel to their effect on cell cycle, ASA and indomethacin also reduced the levels of p34(cdc2) and p33(cdk2), two cyclin-depende nt kinases that are important for cell cycle progression. Finally, all the NSAIDs analyzed, except ASA, induced apoptosis in these cells. Th ere was a rough correlation between the relative potency of these comp ounds in inducing apoptosis and their effectiveness in retarding cell proliferation, Our findings indicate that NSAIDs can reduce the prolif eration of HT-29 colon cancer cells in vitro. In addition, they cause cell cycle quiescence and apoptosis, both of which could account for t heir anti-proliferative effect, These findings suggest possible mechan isms for the cancer preventive effects of these compounds in humans. ( C) 1995 Academic Press, Inc.