Combination of Tumor Necrosis Factor-? with Sulindac in Human Carcinoma Cells in Vivo
Transcription factor NF-?B plays a pivotal role in cancer cells in the resistance to apoptosis, since NF-?B is frequently activated in many primary carcinoma cells. Indeed, several NF-?B inhibitors are found to be promising anti-cancer agents. However, some anti-cancer agents activate NF-?B signals and may reduce their potential, including tumor necrosis factor (TNF)-?. Recently, the nonsteroidal anti-inflammatory drug (NSAID) sulindac and its metabolites have been shown to inhibit the NF-?B-mediated survival signals through inhibition of IKK-? by their direct interaction. We thus investigate whether sulindac and its metabolite can augment TNF-?-mediated apoptosis in human carcinoma cells and be applicable for in vivo clinical usage. We here demonstrate that sulindac inhibited TNF-?-mediated NF-?B activation and greatly enhanced TNF-?-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-? with sulindac compared with TNF-? or sulindac alone. Moreover, we demonstrate that sulindac sulfide further augmented TNF-?-mediated apoptosis. Our data strongly suggest that combination therapy of TNF-? with sulindac and its metabolites may sensitize cancer cells to TNF-? and augment its pro-apoptotic potential. Therefore, in combination with sulindac or its metabolites, TNF-? may become a potentially useful anti-cancer agent to suppress tumor.
sulindac nf-?b apoptosis tnf-? tumor growth suppression