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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.
; 
McGuckin, S.
; 
Hayat, A.
; 
Browne, P. V.
; 
Butini, S.
; 
Campiani, G.
; 
Catherwood, M. A.
; 
Vandenberghe, E.
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Repository DOI
Publication Date
2009-10-13
Keywords
b-cell receptor, in-vitro, bcl-2 phosphorylation, tyrosine kinase, cd38 expression, protein-kinase, up-regulation, cll cells, cml cells, activation
Type
Article
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Citation
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
Abstract
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]
Funder
Publisher
American Association for Cancer Research (AACR)
Publisher DOI
10.1158/0008-5472.can-09-0131
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
cbn
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Externally hosted open access publications with University of Galway authors (2)