Skip to main content

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

Apoptosis volume 10, pages 481–491 (2005)Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Chen LF, Greene WC. Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 2004; 5: 392–401.

    Article  CAS  PubMed  Google Scholar 

  2. Yamamoto Y, Gaynor RB. IkappaB kinases: Key regulators of the NF-kappaB pathway. Trends Biochem Sci2004; 29: 72–79.

    Article  CAS  PubMed  Google Scholar 

  3. Ali S, Mann DA. Signal transduction via the NF-kappaB pathway: A targeted treatment modality for infection, inflammation and repair. Cell Biochem Funct 2004; 22: 67–79.

    Article  CAS  PubMed  Google Scholar 

  4. Romano MF, Lamberti A, Tassone P, et al. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood 1998; 92:9 90–95.

    Google Scholar 

  5. Zaninoni A, Imperiali FG, Pasquini C, Zanella A, Barcellini W. Cytokine modulation of nuclear factor-kappaB activity in B-chronic lymphocytic leukemia. Exp Hematol 2003; 31: 185–190.

    Article  CAS  PubMed  Google Scholar 

  6. Kern C, Cornuel JF, Billard C, et al. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood 2004; 103: 679–688.

    Article  CAS  PubMed  Google Scholar 

  7. Furman RR, Asgary Z, Mascarenhas JO, Liou HC, Schattner EJ. Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. J Immunol 2000; 164: 2200–2206.

    CAS  PubMed  Google Scholar 

  8. Cuni S, Perez-Aciego P, Perez-Chacon G, et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 2004; 18: 1391–1400.

    Article  CAS  PubMed  Google Scholar 

  9. Davis RE, Brown KD, Siebenlist U, et al. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001; 194: 1861–1874.

    Article  CAS  PubMed  Google Scholar 

  10. Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639–16647.

    Article  CAS  PubMed  Google Scholar 

  11. Wright MC, Issa R, Smart DE, et al. Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 2001; 121: 685–698.

    CAS  PubMed  Google Scholar 

  12. Lang A, Schoonhoven R, Tuvia S, et al. Nuclear factor kappaB in proliferation, activation, and apoptosis in rat hepatic stellate cells. J Hepatol 2000; 33: 49–58.

    Article  CAS  PubMed  Google Scholar 

  13. Oakley F, Meso M, Iredale JP, et al. The IKK inhibitor sulfasalazine stimulates JNK-dependent hepatic stellate cell apoptosis and recovery from rat liver fibrosis. Gastroenterology (In press).

  14. Lee JI, Burckart GJ. Nuclear factor kappa B: Important transcription factor and therapeutic target. J Clin Pharmacol 1998; 38: 981–993.

    CAS  PubMed  Google Scholar 

  15. Conaghan PG, Lehmann T, Brooks P. Disease-modifying antirheumatic drugs. Curr Opin Rheumatol 1997; 9: 183–190.

    CAS  PubMed  Google Scholar 

  16. Hanauer SB, Dassopoulos T. Evolving treatment strategies for inflammatory bowel disease. Annu Rev Med 2001; 52: 299–318.

    Article  CAS  PubMed  Google Scholar 

  17. Farr M, Brodrck, Bacon PA. Plasma and synovial fluid concentrations of sulphasalazine and two of its metabolites in rheumatoid arthritis. Rheumatol Int 1985; 5: 247–251.

    Article  CAS  PubMed  Google Scholar 

  18. Schroder H, Campbell DES. Absorption, metabolism and excretion of salicylazosulfapyridine in man. Clin Pharmacol Therapeutics 1972; 13: 539–551.

    CAS  Google Scholar 

  19. Das KM, Eastwood MA, McManus JPA, et al. The metabolism of salicylazosulphapyridine in ulcerative colitis. Gut 1973; 14: 631–641.

    CAS  PubMed  Google Scholar 

  20. Wahl C, Liptay S, Adler G, et al. Sulfasalazine: A potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 1998; 101: 1163–1174.

    CAS  PubMed  Google Scholar 

  21. Weber CK, Liptay S, Wirth T, et al. Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology 2000; 119: 1209–1218.

    CAS  PubMed  Google Scholar 

  22. Ramadas K, Srinivasan N. Iron-ammonium chloride—A convenient and inexpensive reductant. Synth Commun1992; 22: 1389–1395.

    Google Scholar 

  23. Carceller E, Salas J, Merlos M, et al.Novel azo derivatives as prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity. J Med Chem 2001; 44: 3001–3013.

    Article  CAS  PubMed  Google Scholar 

  24. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer 1976; 17: 565–577.

    CAS  PubMed  Google Scholar 

  25. Lanham S, Hamblin T, Oscier D, Ibbotson R, Stevenson F, Packham G. Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood 2003; 101: 1087–1093.

    Article  CAS  PubMed  Google Scholar 

  26. Oakley F, Mann J, Ruddell RG, et al. Basal expression of IkappaBalpha is controlled by the mammalian transcriptional repressor RBP-J (CBF1) and its activator Notch1. J Biol Chem 2003; 278: 24359–24370.

    Article  CAS  PubMed  Google Scholar 

  27. Bertrand-Philippe M, Ruddell RG, Arthur MJ, et al. Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2. J Biol Chem2004; 279: 24530–24539.

    Article  CAS  PubMed  Google Scholar 

  28. Brimmell M, Burns JS, Munson P, et al. High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers. Br J Cancer1999; 81: 1042–1051.

    CAS  PubMed  Google Scholar 

  29. Cahir-McFarland ED, Carter K, Rosenwald A, et al. Role of NF-kB in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells. J Virol 2004; 78: 4108–4119.

    Article  CAS  PubMed  Google Scholar 

  30. Caligaris-Cappio F, Hamblin TJ. B-cell chronic lymphocytic leukemia: A bird of a different feather. J Clin Oncol 1999; 17: 399–408.

    CAS  PubMed  Google Scholar 

  31. Packham G, Stevenson FK. Bodyguards and Assassins; Bcl-2 family protein and control of apoptosis in chronic lymphocytic leukeaemia. Immunology (In press).

  32. Hermisson M, Weller M. NF-kappaB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/ TRAIL-dependent death signaling pathways in human malignant glioma cells. Cell Death Differ 2003; 10: 1078–1089.

    Article  CAS  PubMed  Google Scholar 

  33. Gout PW, Simms CR, Robertson MC. In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine. Anticancer Drugs 2003; 14: 21–29.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research UK Oncology Unit, Cancer Sciences Division, School of Medicine, Southampton General Hospital, University of Southampton, SO16 6YD, UK

    F. Habens & G. Packham

  2. School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK

    N. Srinivasan & A. Ganesan

  3. Division of Infection, Inflammation and Repair, School of Medicine, Southampton General Hospital, University of Southampton, SO16 6YD, UK

    F. Oakley & D. A. Mann

  4. Cancer Research UK Oncology Unit, The Somers Cancer Sciences Building (MP824), Southampton General Hospital, Tremona Road, SO16 6YD, UK

    G. Packham

Authors
  1. F. Habens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Srinivasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Oakley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. A. Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Ganesan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Packham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. Packham.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Habens, F., Srinivasan, N., Oakley, F. et al. Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity. Apoptosis 10, 481–491 (2005). https://doi.org/10.1007/s10495-005-1877-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-005-1877-0

Keywords

  • apoptosis
  • chronic lymphocytic leukaemia
  • fibrosis
  • hepatic stellate cell
  • NF-kB
  • sulfasalazine