The Novel Nuclear Factor-κB Inhibitor LC-1 Is Equipotent in Poor Prognostic Subsets of Chronic Lymphocytic Leukemia and Shows Strong Synergy with Fludarabine

Saman Hewamana, Thet Thet Lin, Chris Jenkins, Alan K Burnett, Craig T Jordan, Chris Fegan, Paul Brennan, Clare Rowntree, Chris Pepper

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Purpose: We have recently shown that the novel nuclear factor-κB (NF-κB) 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. Experimental Design: 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-κB in CLL and identifies the therapeutic potential of LC-1 in combination with fludarabine even in patients with fludarabine resistance.
Original languageEnglish
Pages (from-to)8102-8111
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number24
DOIs
Publication statusPublished - 15 Dec 2008
Externally publishedYes

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