SMAC sensitizes colon cancer cells to apoptosis induced by nonsteroidal antiinflammatory drugs (NSAIDs). Free

A102

Since common epithelial cancers are resistant to most therapeutic treatments, much hope has been placed on chemoprevention. The widely used nonsteroidal antiinflammatory drugs (NSAIDs) are effective in chemoprevention of colorectal cancer. However, the mechanisms underlying the anti-neoplastic effects of NSAIDs remain unclear. The side effects of NSAIDs have presented a significant obstacle for using these agents for cancer prevention in general population. Substantial evidence has indicated that the chemopreventive activities of NSAIDs are mediated by induction of apoptosis. We found that SMAC, a mitochondrial apoptogenic protein, plays an essential role in NSAID-induced apoptosis in colon cancer cells. SMAC is consistently released from the mitochondria into the cytosol during NSAID-induced apoptosis. Deletion of SMAC by homologous recombination or knockdown of SMAC by RNA interference in these cells abrogates NSAID-induced caspase activation and apoptosis. Furthermore, two different small molecules that mimic the function of SMAC, but not their corresponding control compounds, can significantly enhance the apoptotic response to sulindac and indomethacin, NSAIDs commonly used in chemoprevention. SMAC mimetic small molecules can also restore sensitivity to apoptosis in NSAID-resistant colon cancer cells. We found that SMAC functions in NSAID-induced apoptosis by participating in a feed-back amplification loop to promote the release of cytochrome c and other mitochondrial apoptogenic proteins. Together, these results suggest that SMAC may be useful as a target for the development of more effective chemopreventive agents. Manipulation of the apoptotic regulators may help to develop more effective chemopreventive strategies for enhancing chemopreventive efficacy, reducing dose, and decreasing toxicity.