Combination of tumor necrosis factor-α with sulindac augments its apoptotic potential and suppresses tumor growth of human carcinoma cells in nude mice
2003
BACKGROUND
Resistance to apoptosis may be responsible for a principal mechanism by which cancer cells overcome anticancer therapies. Among antiapoptotic signals, the transcription factor, NF-κB, plays a pivotal role in the resistance because it is frequently activated in many primary carcinoma cells. However, NF-κB is also activated by several anticancer therapies, including tumor necrosis factor-alpha (TNF-α). The NF-κB–mediated survival signals are supposed to evade these therapies. Recently, a nonsteroidal antiinflammatory drug, sulindac, and its metabolites have been shown to inhibit the NF-κB pathway and to enhance TNF-α–mediated apoptosis in lung carcinoma cell lines. In the current study, the authors investigated whether sulindac can augment TNF-α–mediated apoptosis in other human carcinoma cells and whether it can be applied for in vivo clinical usage.
METHODS
Human gastric MKN45 and cervical HeLa carcinoma cells were treated with sulindac and/or TNF-α. Proapoptotic effects of these agents were evaluated by trypan blue exclusion assay, DNA fragmentation, and caspase-3 activity. The effect of sulindac on NF-κB activation was evaluated by luciferase reporter and gel-shift assays. The suppressive effects of these reagents on the subcutaneous tumor growth of MKN45 cells were evaluated by measuring tumor size in nude mice.
RESULTS
Sulindac inhibited TNF-α–mediated NF-κB activation and greatly sensitized MKN45 and HeLa cell lines to TNF-α. Moreover, in vivo tumor growth of MKN45 cells was inhibited most strongly by a combination of TNF-α with sulindac compared with TNF-α or sulindac alone.
CONCLUSIONS
The current study data strongly suggest that combination therapy of TNF-α with sulindac may sensitize tumor cells to TNF-α and augment its proapoptotic potential. Therefore, in combination with sulindac, TNF-α may become a potentially useful anticancer agent to suppress tumor growth in a wide range of carcinomas. Cancer 2003;97:1412–20. © 2003 American Cancer Society.
DOI 10.1002/cncr.11210
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