ASPIRIN TOXICITY FOR HUMAN COLONIC TUMOR-CELLS RESULTS FROM NECROSIS AND IS ACCOMPANIED BY CELL-CYCLE ARREST

Chemoprevention of colorectal cancer using aspirin has been demonstrat ed in rodents and has been suggested by data from epidemiological stud ies. The mechanism that accounts for this prevention is unknown, but i t is thought to relate to an irreversible inhibition of cyclooxygenase and, subsequently, prostaglandin production, The effect of aspirin on the growth of human colonic tumor cells was determined in an effort t o gain insight into a possible mechanism of action. In the two cell li nes studied, SW 620 and HT-29, we observed a significant dose-and time -dependent increase in aspirin toxicity in a concentration range of 1. 25-10 mM. This result was independent of prostaglandin production, bec ause there was no measurable prostaglandin E-2 in cell culture medium. As compared with controls, cells in cultures that contained aspirin w ere not detached, which suggests that the mechanism of cell death was not apoptosis, Flow cytometric analysis revealed an increase in S phas e and G(2)-M populations as well as the number of subdiploid nuclei in cultures treated with high-dose aspirin. Confirmation that cells were undergoing necrosis in response to aspirin was evident from the prese nce of cells that bound annexin V and accumulated propidium iodide in the absence of a population that bound annexin atone. The results sugg est that aspirin induces cell cycle arrest and causes necrosis at high concentrations in vitro, but does not induce apoptosis, Collectively, these two events, necrosis and cell cycle arrest, may contribute to t he chemopreventive effect that seems to result from long-term administ ration of aspirin in vivo.