Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity

Abstract

The NF-kB transcription factor plays a key role in the regulation of apoptosis by modulating expression of a wide range of cell death control molecules. NF-kB also plays an important role in human diseases by promoting inappropriate cell survival. Small molecule inhibitors of NF-kB are therefore likely to provide novel therapeutic opportunities. Sulfasalazine (SFZ) is a synthetic anti-inflammatory comprising an aminosalicylate, 5-amino salicylic acid (5-ASA), linked to an antibiotic, sulfapyridine (SPY). SFZ, but not 5-ASA or SPY, inhibits activation of NF-kB. We synthesised a small number of SFZ analogues and determined their ability to inhibit NF-kB activity and promote apoptosis in chronic lymphocytic leukaemia and hepatic stellate cells, where NF-kB plays an important role in cell survival. Remarkably, 3 of the 6 analogues synthesised were significantly more effective (up to 8-fold) inhibitors of NF-kB dependent transcription and this increased activity was associated with enhanced apoptosis. Therefore, it is possible to readily improve the NF-kB inhibiting activity of SFZ and analogues of SFZ may be attractive therapeutic agents for malignancies and chronic liver disease where NF-kB is thought to play a significant role.

Mechanisms of Hepatic Fibrogenesis

“…Interestingly, sulfasalazine inhibits the kinase (inhibitor kappa kinase, IκK) that activates IκB, and thus may accelerate recovery from experimental fibrosis by clearance of activated stellate cells through apoptosis. 94,96 Because these activated cells typically express high levels of TIMP-1, a metalloproteinase inhibitor, their clearance leads to increased net activity of matrix degrading proteases.…”

“…Interestingly, sulfasalazine inhibits the kinase (inhibitor kappa kinase, IκK) that activates IκB, and thus may accelerate recovery from experimental fibrosis by clearance of activated stellate cells through apoptosis. 94,96 Because these activated cells typically express high levels of TIMP-1, a metalloproteinase inhibitor, their clearance leads to increased net activity of matrix degrading proteases.Finally, messenger RNA (mRNA) stabilization also contributes to increased gene expression during stellate cell activation. Specifically, there is a 16-fold increase in collagen alpha 1(I) mRNA stabilization during stellate cell activation as a result of interaction of a specific protein, αCP, to a specific sequence in the 3′ untranslated region of the mRNA, 97 and also involving the interaction of a 120-kilodalton protein with the 5′ stem-loop structure.…”

Proteasome inhibition induces hepatic stellate cell apoptosis

“…10 Although it has been reported that NF-B inhibition does not result in HSC apoptosis, 7 several studies have indicated that NF-B inhibition is a potent mechanism to induce HSC apoptosis. 8,11 Thus, mechanisms to inhibit NF-B in HSC have potential therapeutic relevance.…”

Small molecules in stem cell self-renewal and differentiation

“…Kanzler et al 79 recently compiled more than 40 compounds that act on Toll-like receptors that are in clinical trials for treatment of certain cancers, such as breast cancer and melanoma; allergies to ragweed, dust mites and asthma; and infectious diseases, such as HIV and Hepatitis C. NF-kB is known for its role in controlling apoptosis, so it comes as no surprise that the transcription factor is involved in the development of certain cancer types. Constitutive activation of NF-kB is linked to malignancies such as multiple myeloma, chronic lymphocytic leukemia and several lymphomas; 30 therefore, small molecules which can modulate NF-kB activity may be potent therapeutics for certain cancers. Habens et al 30 demonstrate the effectiveness of sulfasalazine (SFZ) a synthetic small molecule, as an inhibitor of IKK, which also results in the inhibition of NF-kB and subsequent apoptosis.…”

“…Constitutive activation of NF-kB is linked to malignancies such as multiple myeloma, chronic lymphocytic leukemia and several lymphomas; 30 therefore, small molecules which can modulate NF-kB activity may be potent therapeutics for certain cancers. Habens et al 30 demonstrate the effectiveness of sulfasalazine (SFZ) a synthetic small molecule, as an inhibitor of IKK, which also results in the inhibition of NF-kB and subsequent apoptosis. Additionally, they showed that certain SFZ analogues produced compounds that are even more highly effective in inducing apoptosis in chronic lymphocytic leukemia cells in vitro.…”