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The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

¹ John Durkan Research Laboratories, Institute of Molecular Medicine, and ² School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland; ³ Department of Haematology, St. James's Hospital, Dublin, Ireland; ⁴ European Research Centre for Drug Discovery and Development, University of Siena, Siena, Italy; ⁵ Department of Haematology, Belfast City Hospital, Belfast, Northern Ireland; and ⁶ Department of Haematology, University College Hospital, Galway, Ireland

Requests for reprints: Tony McElligott, Institute of Molecular Medicine, Trinity Centre, St. James's Hospital, Dublin 8, Ireland. Phone: 353-1-896-3276; Fax: 353-1-410-3476. E-mail: tony.mcelligott{at}tcd.ie.

Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC₅₀ of 0.55 µmol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV_H genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15–induced apoptosis. Pharmacologic inhibition of c-jun NH₂-terminal kinase inhibited PBOX-15–induced apoptosis in mutated IgV_H and ZAP-70^– CLL cells but not in unmutated IgV_H and ZAP-70⁺ cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential. [Cancer Res 2009;69(21):8366–75]

Key Words: CLL • tubulin depolymerization agent • caspase-8 • JNK