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Apoptosis

, Volume 10, Issue 3, pp 481–491 | Cite as

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

  • F. Habens
  • N. Srinivasan
  • F. Oakley
  • D. A. Mann
  • A. Ganesan
  • G. PackhamEmail author
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.

Keywords

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

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • F. Habens
    • 1
  • N. Srinivasan
    • 2
  • F. Oakley
    • 3
  • D. A. Mann
    • 3
  • A. Ganesan
    • 2
  • G. Packham
    • 1
    • 4
    Email author
  1. 1.Cancer Research UK Oncology Unit, Cancer Sciences Division, School of Medicine, Southampton General HospitalUniversity of SouthamptonUK
  2. 2.School of ChemistryUniversity of SouthamptonSouthamptonUK
  3. 3.Division of Infection, Inflammation and Repair, School of Medicine, Southampton General HospitalUniversity of SouthamptonUK
  4. 4.Cancer Research UK Oncology Unit, The Somers Cancer Sciences Building (MP824)Southampton General HospitalUK

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