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Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been shown to suppress transcription factor NF-?B, which controls the expression of genes such as cyclooxygenase (COX)-2 and cyclin D1, leading to inhibition of proliferation of tumor cells. There is no systematic study as to how these drugs differ in their ability to suppress NF-?B activation and NF-?B-regulated gene expression or cell proliferation. In the present study, we investigated the effect of almost a dozen different commonly used NSAIDs on tumor necrosis factor (TNF)-induced NF-?B activation and NF-?B-regulated gene products, and on cell proliferation. Dexamethasone, an anti-inflammatory steroid, was included for comparison with NSAIDs. As indicated by DNA binding, none of the drugs alone activated NF-?B. All compounds inhibited TNF-induced NF-?B activation, but with highly variable efficacy. The 50%inhibitory concentration required was 5.67, 3.49, 3.03, 1.25, 0.94, 0.60, 0.38, 0.084, 0.043, 0.027, 0.024, and 0.010?mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. All drugs inhibited I?Bakinase and suppressed I?Badegradation and NF-?B-regulated reporter gene expression. They also suppressed NF-?B-regulated COX-2 and cyclin D1 protein expression in a dose-dependent manner. All compounds inhibited the proliferation of tumor cells, with 50%inhibitory concentrations of 6.09, 1.12, 0.65, 0.49, 1.01, 0.19, 0.36, 0.012, 0.016, 0.047, 0.013, and 0.008?mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. Overall these results indicate that aspirin and ibuprofen are least potent, while resveratrol, curcumin, celecoxib, and tamoxifen are the most potent anti-inflammatory and antiproliferative agents of those we studied.Oncogene (2004) 23, 9247-9258. doi:10.1038/sj.onc.1208169 Published online 18 October 2004 [ABSTRACT FROM AUTHOR]

Adenosine is an endogenous immunomodulator that has been shown to exhibit anti-inflammatory and immunosuppressive properties through a mechanism that is not fully established. Owing to the pivotal role of nuclear factor (NF)-?B in these responses, we tested the hypothesis that adenosine mediates its effects through suppression of NF-?B activation. We investigated the effects of adenosine on NF-?B activation induced by various inflammatory agents in human myeloid KBM-5 cells. The treatment of these cells with adenosine suppressed TNF-induced NF-?B activation, but had no effect on activation of another redox-sensitive transcription factor, AP-1. These effects were not restricted to myeloid cells, as NF-?B activation in other lymphocytic and epithelial cell types was also inhibited. The effect on TNF-induced NF-?B activation was selective as adenosine had minimal effect on NF-?B activation induced by H2O2, PMA, LPS, okadaic acid, or ceramide, suggesting differences in the pathway leading to NF-?B activation by different agents. Adenosine also suppressed NF-?B-dependent reporter gene expression activated by TNF or by overexpression of TNFR1, TRAF 2, NIK, and p65 subunit of NF-?B. The suppression of TNF-induced NF-?B activation by adenosine was found not to be because of inhibition of TNF-induced I?Ba phosphorylation and degradation or I?Ba kinase activation. The suppression of TNF-induced NF-?B activation was unique to adenosine, as neither its metabolites (inosine, AMP, and ATP) nor pyrimidines (thymidine and uridine) had any effect. Overall, our results clearly demonstrate that adenosine selectively suppresses TNF-induced NF-?B activation, which may contribute to its role in suppression of inflammation and of the immune system.Oncogene (2003) 22, 1206-1218. doi:10.1038/sj.onc.1206184 [ABSTRACT FROM AUTHOR]