The novel tubulin-targeting agent pyrrolo-1,5-benzoxazepine-15 induces apoptosis in poor prognostic subgroups of chronic lymphocytic leukemia
McElligott, A. M.
Maginn, E. N.
Greene, L. M.
Browne, P. V.
Catherwood, M. A.
Williams, D. C.
Zisterer, D. M.
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McElligott, A. M. Maginn, E. N.; Greene, L. M.; McGuckin, S.; Hayat, A.; Browne, P. V.; Butini, S.; Campiani, G.; Catherwood, M. A.; Vandenberghe, E.; Williams, D. C.; Zisterer, D. M.; Lawler, M. (2009). The novel tubulin-targeting agent pyrrolo-1,5-benzoxazepine-15 induces apoptosis in poor prognostic subgroups of chronic lymphocytic leukemia. Cancer Research 69 (21), 8366-8375
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 mu mol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV(II) 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(II) and ZAP-70(-) CLL cells but not in unmutated IgV(II) 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]