대한대장항문학회

PURPOSE: One of possible mechanisms of the antineoplastic effect by nonsteroidal anti-inflammatory drugs (NSAIDs) is an induction of apoptosis. The NSAIDs-induced apoptosis appears to be caspase- and mitochondria-dependent. The ubiquitin-proteasome<br>system, which is a fundamental non-lysosomal tool that cells use to process or degrade a variety of short-lived proteins, is known to be involved in apoptosis and to be located upstream of mitochondrial changes and caspase activation. The present study<br>was conducted to explore the potential role of proteasome pathway in NSAIDs-induced apoptosis. METHODS: We employed sulindac as a NSAID, and the lactacystin as a proteasome inhibitor to investigate the extent of the apoptosis in colon cancer cell line,<br>HT-29 cells. The proteasome activity and the amount of apoptosis were quantified after cells were treated with 1 mM sulindac, 1 micro m lactacystin or both. RESULTS: Sulindac treatment caused apoptosis of the HT-29 cells in a time-dependent manner with<br>resultant changes in nuclear morphology. Western blots also showed caspase-3 activation and PARP cleavage after sulindac treatment. Not only single treatment with lactacystin decreased proteasome activity, but co-treatment with sulindac enhanced<br>decrease in proteasome activity further (P < 0.01). Treatment with lactacystin only did not induce apoptosis. However, lactacystin augmented the induction of sulindac-induced apoptosis (P < 0.01). This synergistic effect was also proven by Western blot<br>analyses, where co-treatment augmented the caspase-3 activation and PARP degradation. CONCLUSIONS: The combination treatment of sulindac with a proteasome inhibitor lactacystin is suggested to be a very effective strategy for the induction of cancer<br>cell apoptosis. Elucidation of the mechanism underlying the regression of colon cancers by combination of sulindac and lactacystin seems to be an immediate challenge in the near future.<br>