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

Authors' Affiliations: Departments of ¹ Haematology and ² Medical Biochemistry and Immunology, School of Medicine, Cardiff University, and ³ Department of Haematology, University Hospital of Wales, Cardiff, United Kingdom; and ⁴ Division of Haematology/Oncology, University of Rochester School of Medicine, Rochester, New York

Requests for reprints: Saman Hewamana, Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom. Phone: 44-29-20747747; Fax: 44-29-20744655; E-mail: hewamanas{at}cf.ac.uk.

Purpose: We have recently shown that the novel nuclear factor-B (NF-B) 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-B in CLL and identifies the therapeutic potential of LC-1 in combination with fludarabine even in patients with fludarabine resistance.