The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia
| Autor: | Paul Browne, Mark Catherwood, Lisa M. Greene, Mark Lawler, D. Clive Williams, Elaina N. Maginn, Amjad Hayat, Elisabeth Vandenberghe, Stefania Butini, Daniela M. Zisterer, Anthony M. McElligott, Siobhan McGuckin, Giuseppe Campiani |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Chronic lymphocytic leukemia protein-kinase Apoptosis CD38 Microtubules Tubulin hemic and lymphatic diseases DNA (Cytosine-5-)-Methyltransferases Cytotoxicity Aged 80 and over Caspase 8 ZAP-70 Protein-Tyrosine Kinase cml cells tyrosine kinase Middle Aged Prognosis Fludarabine Leukemia Haematopoiesis Oncology Female cd38 expression Immunoglobulin Heavy Chains bcl-2 phosphorylation Vidarabine medicine.drug Adult Immunoblotting B-cell receptor Antineoplastic Agents in-vitro Biology medicine up-regulation Humans Pyrroles Aged cll cells b-cell receptor JNK Mitogen-Activated Protein Kinases Granulocyte-Macrophage Colony-Stimulating Factor medicine.disease Leukemia Lymphocytic Chronic B-Cell Oxazepines Immunology Cancer research activation |
| Zdroj: | Cancer Research. 69:8366-8375 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-09-0131 |
| Popis: | 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 IgVH 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 IgVH and ZAP-70− CLL cells but not in unmutated IgVH 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] |
| Databáze: | OpenAIRE |
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