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-kappab, plays a pivotal role in the resistance because it is frequently activated in many primary carcinoma cells. however, nf-kappab is also activated by several anticancer therapies, including tumor necrosis factor-alpha (tnf-alpha). the nf-kappab-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-kappab pathway and to enhance tnf-alpha-mediated apoptosis in lung carcinoma cell lines. in the current study, the authors investigated whether sulindac can augment tnf-alpha-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-alpha. proapoptotic effects of these agents were evaluated by trypan blue exclusion assay, dna fragmentation, and caspase-3 activity. the effect of sulindac on nf-kappab 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-alpha-mediated nf-kappab activation and greatly sensitized mkn45 and hela cell lines to tnf-alpha. moreover, in vivo tumor growth of mkn45 cells was inhibited most strongly by a combination of tnf-alpha with sulindac compared with tnf-alpha or sulindac alone.
Conclusions:
The current study data strongly suggest that combination therapy of tnf-alpha with sulindac may sensitize tumor cells to tnf-alpha and augment its proapoptotic potential. therefore, in combination with sulindac, tnf-alpha may become a potentially useful anticancer agent to suppress tumor growth in a wide range of carcinomas.