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- Title
Combination of Tumor Necrosis Factor-a with Sulindac in Human Carcinoma Cells in Vivo.
- Authors
YASUI, HIROSHI; ADACHI, MASAAKI; IMAI, KOHZOH
- Abstract
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.
- Subjects
NONSTEROIDAL anti-inflammatory agents; APOPTOSIS; TUMOR necrosis factors; CANCER; METABOLITES; TRANSCRIPTION factors; CELL death; CELL culture; TUMOR growth
- Publication
Annals of the New York Academy of Sciences, 2004, Vol 1010, Issue 1, p273
- ISSN
0077-8923
- Publication type
Article
- DOI
10.1196/annals.1299.047