EFFECTS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON PROLIFERATION AND ON INDUCTION OF APOPTOSIS IN COLON-CANCER CELLS BY A PROSTAGLANDIN-INDEPENDENT PATHWAY

Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence o f and mortality from colon cancer. We observed that NSAIDs inhibit the proliferation rate, alter the cell cycle distribution, and induce apo ptosis in colon cancer cell lines. We evaluated whether the inhibition by NSAIDs of prostaglandin (PG) synthesis is required for their effec ts on colon cancer cells by studying two human colon cancer cell lines : HCT-15 and HT-29. HCT-15, which lacks cyclooxygenase transcripts, do es not produce PGs even when exogenously stimulated, whereas HT-29 pro duces PGE(2), PGF(2 alpha), and PGI(2). HCT-15 and HT-29 cells, when t reated for up to 12 hr with 200 mu M sulindac sulfide (an active metab olite of sulindac) or 900 mu M piroxicam, showed changes in proliferat ion, cell cycle phase distribution, and apoptosis. Treatment with PGE( 2), PGF(2 alpha), and PGI(2), following a variety of protocols, and at concentrations between 10(-6) and 10(-11) M, failed to reverse the ef fects of NSAIDs on these three parameters of cell growth. We concluded that NSAIDs inhibit the proliferation rate of the two colon cancer ce ll lines independent of their ability to inhibit PG synthesis. Thus, a lternative mechanisms for their activity on tumor cell growth must be entertained. These observations may be relevant to the mechanism of co lon tumor inhibition by NSAIDs.