PubMed · 3264638
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J Friis. 1988-10-17. [Tenoxicam].. https://pubmed.ncbi.nlm.nih.gov/3264638/
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Nonsteroidal anti-inflammatory drug (NSAID)-induced apoptosis is considered to be an important mechanism in the antineoplastic effects and damage produced by the drugs in the gastrointestinal tract. In this study, two different gastric cancer cell lines, MKN28 (mutant-type p53) and AGS (wild-type p53), were compared as to growth inhibition, apoptosis, and cell cycle and apoptosis-related gene expression in response to indomethacin treatment. Cell growth was measured by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Apoptosis was characterized by acridine orange staining and DNA fragmentation, and cell cycle kinetics by flow cytometry. The mRNA and protein levels of p53, p21waf1/cip1, and c-myc were determined by Northern and Western blotting. The results showed that indomethacin initiated growth inhibition and apoptosis in both cell lines without cell cycle shifting. AGS cells were more sensitive to growth inhibitory activity and apoptosis of indomethacin than MKN28 cells. In MKN28 cells, the levels of p53, p21waf1/cip1, and c-myc mRNA remained unchanged over the 24-hr treatment with indomethacin, but the p53 protein level was elevated after 4 hr. There was no change in the p21waf1/cip1 and c-myc protein levels in the MKN28 cells. In AGS cells, a progressive increase in c-myc mRNA and protein levels was noted, while p53 and p21waf1/cip1 remained unchanged. It can be concluded that wild-type p53 and/or up-regulation of c-myc is associated with indomethacin-mediated differential apoptosis in gastric epithelial cells.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the proliferation of colorectal carcinoma cell lines in vitro and reduce the risk of colorectal carcinoma in vivo. The good correlation observed between the potency of NSAIDs as inhibitors of colorectal carcinoma cell proliferation and as antagonists of a 78 kDa gastrin binding protein (GBP) suggested that blockade of the GBP might contribute to the anti-proliferative effects of NSAIDs [G.S. Baldwin, V.J. Murphy, Z. Yang, T. Hashimoto, J. Pharmacol. Exp. Ther. 286 (1998) 1110-1114]. The most potent NSAID investigated was sulindac sulphide, which had an IC50 value of 40 microM. In order to investigate the structural requirements for binding to the GBP, 26 analogues of sulindac sulphide and sulindac sulphoxide were tested for their ability to inhibit the binding of iodinated gastrin to the GBP. Six of the analogues inhibited gastrin binding by more than 50% at a concentration of 1 mM. The IC50 values estimated by computer fitting of titration data were in the range of 280-940 microM. Comparison of the analogue structures suggests that a substituent with a carboxyl group is preferred in the R2 position. In addition the location of the NSAID binding site within the GBP structure was investigated. NSAIDs bound to both the N- and C-terminal halves of the GBP, and the affinities determined were similar to the values previously reported for the full-length GBP. The results reported herein represent the first step in the rational design of more potent GBP antagonists, some of which may be useful for the treatment of colorectal carcinoma.
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