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. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11210
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 humancarcinoma 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. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11210
Authors: Keiji Minagawa; Mohamed R Berber; Inas H Hafez; Takeshi Mori; Masami Tanaka Journal: J Mater Sci Mater Med Date: 2012-02-18 Impact factor: 3.896
Authors: Wei Zou; Kevin M Beggs; Erica M Sparkenbaugh; A Daniel Jones; Husam S Younis; Robert A Roth; Patricia E Ganey Journal: J Pharmacol Exp Ther Date: 2009-07-28 Impact factor: 4.030