title: The novel nuclear factor-kappaB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine.
abstract: OBJECTIVE
  We have recently shown that the novel nuclear factor-kappaB (NF-kappaB) inhibitor LC-1 is effective in primary chronic lymphocytic leukemia (CLL) cells. Here we elucidated the mechanism of action of LC-1, evaluated its relative cytotoxicity in prognostic subsets, and investigated its potential synergistic interaction with fludarabine.
  
  
  METHODS
  Ninety-six fully characterized CLL cases were assessed for in vitro sensitivity to LC-1 and fludarabine. In selected cases, caspase activation, inhibition of Rel A DNA binding, and the transcription of CFLAR, BIRC5, and BCL2 were measured before and after exposure to LC-1. In addition, the efficacy of LC-1 was assessed in the presence of the survival factors CD154 and interleukin-4, and the potential synergistic interaction between LC-1 and fludarabine was evaluated.
  
  
  RESULTS
  Cell death was associated with caspase-3 activation mediated via activation of both caspase-8 and caspase-9. Apoptosis was preceded by a reduction of nuclear Rel A DNA binding and inhibition of CFLAR, BIRC5, and BCL2 transcription. Importantly, LC-1 overcame the cytoprotective effects by interleukin-4 and CD40 ligand and was equipotent in CLL cells derived from good and bad prognostic subsets. LC-1 exhibited strong synergy with fludarabine, and the combination produced a highly significant mean dose reduction index for fludarabine of > 1,000.
  
  
  CONCLUSIONS
  In view of imminent first-in-man study of LC-1 in Cardiff, these data show an important mechanistic rationale for the use of LC-1 in this disease. Furthermore, it validates the concept of targeting nuclear factor-kappaB in CLL and identifies the therapeutic potential of LC-1 in combination with fludarabine even in patients with fludarabine resistance.
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom. hewamanas@cf.ac.uk
authors.forename: Saman
authors.initials: S
authors.lastname: Hewamana
authors.forename: Thet Thet
authors.initials: TT
authors.lastname: Lin
authors.forename: Chris
authors.initials: C
authors.lastname: Jenkins
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Clare
authors.initials: C
authors.lastname: Rowntree
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D023201:CD40 Ligand / Q000494:pharmacology; D019610:Cytoprotection; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011379:Prognosis; D012717:Sesquiterpenes / Q000494:pharmacology*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C524858:LC-1 compound; D016328:NF-kappa B; D012717:Sesquiterpenes; D023201:CD40 Ligand; D015847:Interleukin-4; D004247:DNA; D014740:Vidarabine; C024352:fludarabine