title: The novel tubulin-targeting agent pyrrolo-1,5-benzoxazepine-15 induces apoptosis in poor prognostic subgroups of chronic lymphocytic leukemia.
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 IC(50) of 0.55 micromol/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 NH(2)-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.
authors.affiliation: John Durkan Research Laboratories, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. tony.mcelligott@tcd.ie
authors.forename: Anthony M
authors.initials: AM
authors.lastname: McElligott
authors.forename: Elaina N
authors.initials: EN
authors.lastname: Maginn
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.forename: Siobhan
authors.initials: S
authors.lastname: McGuckin
authors.forename: Amjad
authors.initials: A
authors.lastname: Hayat
authors.forename: Paul V
authors.initials: PV
authors.lastname: Browne
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Mark A
authors.initials: MA
authors.lastname: Catherwood
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Vandenberghe
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Mark
authors.initials: M
authors.lastname: Lawler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007143:Immunoglobulin Heavy Chains / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008870:Microtubules / Q000187:drug effects; D008875:Middle Aged; D010077:Oxazepines / Q000494:pharmacology*; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: C514160:4-acetoxy-5-(1-(naphthyl))naphtho(2,3-b)pyrrolo(2,1-d)(1,4)oxazepine; D000970:Antineoplastic Agents; D007143:Immunoglobulin Heavy Chains; D010077:Oxazepines; D011758:Pyrroles; D014404:Tubulin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004248:DNA (Cytosine-5-)-Methyltransferases; D051746:ZAP-70 Protein-Tyrosine Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D053181:Caspase 8; D014740:Vidarabine; C024352:fludarabine