| Autor: |
McElligott AM; John Durkan Research Laboratories, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. tony.mcelligott@tcd.ie, Maginn EN, Greene LM, McGuckin S, Hayat A, Browne PV, Butini S, Campiani G, Catherwood MA, Vandenberghe E, Williams DC, Zisterer DM, Lawler M |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer research [Cancer Res] 2009 Nov 01; Vol. 69 (21), pp. 8366-75. Date of Electronic Publication: 2009 Oct 13. |
| DOI: |
10.1158/0008-5472.CAN-09-0131 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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