Combination of Tumor Necrosis Factor‐α with Sulindac in Human Carcinoma Cells in Vivo

A bstract : Transcription factor NF‐κB plays a pivotal role in cancer cells in the resistance to apoptosis, since NF‐κB is frequently activated in many primary carcinoma cells. Indeed, several NF‐κB inhibitors are found to be promising anti‐cancer agents. However, some anti‐cancer agents activate NF‐κB signals and may reduce their potential, including tumor necrosis factor (TNF)‐α. Recently, the nonsteroidal anti‐inflammatory drug (NSAID) sulindac and its metabolites have been shown to inhibit the NF‐κB‐mediated survival signals through inhibition of IKK‐β by their direct interaction. We thus investigate whether sulindac and its metabolite can augment TNF‐α‐mediated apoptosis in human carcinoma cells and be applicable for in vivo clinical usage. We here demonstrate that sulindac inhibited TNF‐α‐mediated NF‐κB activation and greatly enhanced TNF‐α‐induced apoptosis in human gastric MKN45 and cervical HeLa carcinoma cell lines. The in vivo tumor growth of MKN45 cells was most strongly inhibited by a combination of TNF‐α with sulindac compared with TNF‐α or sulindac alone. Moreover, we demonstrate that sulindac sulfide further augmented TNF‐α‐mediated apoptosis. Our data strongly suggest that combination therapy of TNF‐α with sulindac and its metabolites may sensitize cancer cells to TNF‐α and augment its pro‐apoptotic potential. Therefore, in combination with sulindac or its metabolites, TNF‐α may become a potentially useful anti‐cancer agent to suppress tumor.