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

Abstract

<div>Abstract<p>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 (<i>n</i> = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (<i>n</i> = 19) in a dose-dependent manner, with mean IC<sub>50</sub> of 0.55 μmol/L. PBOX-15 significantly induced apoptosis in CLL cells (<i>n</i> = 46) including cells with poor prognostic markers: unmutated IgV<sub>H</sub> 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 NH<sub>2</sub>-terminal kinase inhibited PBOX-15–induced apoptosis in mutated IgV<sub>H</sub> and ZAP-70<sup>−</sup> CLL cells but not in unmutated IgV<sub>H</sub> and ZAP-70<sup>+</sup> 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]</p></div>