Sulindac Inhibits Activation of the NF-κB Pathway

Abstract

Sulindac is a non-steroidal anti-inflammatory agent that is related both structurally and pharmacologically to indomethacin. In addition to its anti-inflammatory properties, sulindac has been demonstrated to have a role in the prevention of colon cancer. Both its growth inhibitory and anti-inflammatory properties are due at least in part to its ability to decrease prostaglandin synthesis by inhibiting the activity of cyclooxygenases. Recently, we demonstrated that both aspirin and sodium salicylate, but not indomethacin, inhibited the activity of an IκB kinase β (IKKβ) that is required to activate the nuclear factor-κB (NF-κB) pathway. In this study, we show that sulindac and its metabolites sulindac sulfide and sulindac sulfone can also inhibit the NF-κB pathway in both colon cancer and other cell lines. Similar to our previous results with aspirin, this inhibition is due to sulindac-mediated decreases in IKKβ kinase activity. Concentrations of sulindac that inhibit IKKβ activity also reduce the proliferation of colon cancer cells. These results suggest that the growth inhibitory and anti-inflammatory properties of sulindac may be regulated in part by inhibition of kinases that regulate the NF-κB pathway. Sulindac is a non-steroidal anti-inflammatory agent that is related both structurally and pharmacologically to indomethacin. In addition to its anti-inflammatory properties, sulindac has been demonstrated to have a role in the prevention of colon cancer. Both its growth inhibitory and anti-inflammatory properties are due at least in part to its ability to decrease prostaglandin synthesis by inhibiting the activity of cyclooxygenases. Recently, we demonstrated that both aspirin and sodium salicylate, but not indomethacin, inhibited the activity of an IκB kinase β (IKKβ) that is required to activate the nuclear factor-κB (NF-κB) pathway. In this study, we show that sulindac and its metabolites sulindac sulfide and sulindac sulfone can also inhibit the NF-κB pathway in both colon cancer and other cell lines. Similar to our previous results with aspirin, this inhibition is due to sulindac-mediated decreases in IKKβ kinase activity. Concentrations of sulindac that inhibit IKKβ activity also reduce the proliferation of colon cancer cells. These results suggest that the growth inhibitory and anti-inflammatory properties of sulindac may be regulated in part by inhibition of kinases that regulate the NF-κB pathway. nuclear factor-κB IκB kinase inhibitor of κB NF-κB inducing kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 glutathione S-transferase tumor necrosis factor α phosphate-buffered saline stress-activated protein kinase extracellular response kinase 2 human immunodeficiency virus amino acids mitogen-activated protein. The NF-κB1 pathway regulates the cellular response to a variety of stimuli including cytokines, bacterial and viral infection, and activation of cellular stress pathways (reviewed in Refs. 1Baeuerle P.A. Baltimore D. Cell. 1996; 87: 13-20Abstract Full Text Full Text PDF PubMed Scopus (2910) Google Scholar and 2Baldwin A.S. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5515) Google Scholar). The NF-κB pathway is also critical for the control of cellular growth properties (3Lu X. Xie W. Reed D. Bradshaw W.S. Simmons D.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7961-7965Crossref PubMed Scopus (195) Google Scholar, 4Wang C.Y. Mayo M.W. Korneluk R.G. Goeddel D.V. Baldwin Jr., A.S. Science. 1998; 281: 1680-1683Crossref PubMed Scopus (2552) Google Scholar, 5Beg A.A. Sha W.C. Bronson R.T. Ghosh S. Baltimore D. Nature. 1995; 376: 167-170Crossref PubMed Scopus (1620) Google Scholar, 6Chu Z.-L. McKinsey T.A. Liu L. Gentry J.J. Malim M.H. Ballard D.W. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10057-10062Crossref PubMed Scopus (819) Google Scholar, 7Wu M. Lee H. Bellas R.E. Schauer S.L. Arsura M. Katz D. FitzGerald M.J. Rothstein T.L. Sherr D.H. Sonenshein G.E. EMBO J. 1996; 15: 4682-4690Crossref PubMed Scopus (553) Google Scholar). For example, disruption of the gene encoding the p65 member of the NF-κB family leads to severe hepatic apoptosis indicating that at least in some cell types that NF-κB is a critical anti-apoptotic factor (5Beg A.A. Sha W.C. Bronson R.T. Ghosh S. Baltimore D. Nature. 1995; 376: 167-170Crossref PubMed Scopus (1620) Google Scholar). Inhibition of apoptosis is likely mediated by NF-κB induction of cellular genes such as cellular inhibitor of apoptosis-1 and -2 which inhibit the apoptotic process (4Wang C.Y. Mayo M.W. Korneluk R.G. Goeddel D.V. Baldwin Jr., A.S. Science. 1998; 281: 1680-1683Crossref PubMed Scopus (2552) Google Scholar, 6Chu Z.-L. McKinsey T.A. Liu L. Gentry J.J. Malim M.H. Ballard D.W. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10057-10062Crossref PubMed Scopus (819) Google Scholar). The fact that high constitutive levels of NF-κB are found in the nucleus of some tumors further implicates activation of this pat