| Autor: |
Hayden, R. E., Pratt, G., Davies, N. J., Khanim, F. L., Birtwistle, J., Delgado, J., Pearce, C., Sant, T., Drayson, M. T., Bunce, C. M. |
| Předmět: |
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| Zdroj: |
Leukemia (08876924); Feb2009, Vol. 23 Issue 2, p292-304, 13p, 7 Graphs |
| Abstrakt: |
B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in older adults, remains largely incurable and novel treatments are urgently required. We previously reported powerful pro-apoptotic actions of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against Burkitts lymphoma cells. Here, we demonstrate that BEZ and MPA individually, and more potently when combined (BEZ+MPA), induce apoptosis of unsorted and CD19+ve-selected CLL cells and abrogate the pro-proliferative activity of CD40L. This action was tumor cell specific, as the drugs had little impact on normal donor cells. The antiproliferative actions of BEZ+MPA were associated with the generation of reactive oxygen species (ROS), and the proapoptotic actions were associated with the generation of both ROS and mitochondrial superoxide (MSO). BEZ increased prostaglandin D2 (PGD2) synthesis by CLL cells, and treatment with PGD2 and its antineoplastic derivative 15dΔ12,14,PGJ2 recapitulated BEZ-induced antiproliferative and proapoptotic actions. The PGD2 receptor antagonist, BW868C, did not block BEZ or PGD2 activity against CLL cells. The potency of BEZ+MPA against CLL cells mirrored that of chlorambucil, and BEZ+MPA combined with chlorambucil was more potent than either treatment alone. Given the known safety profiles of BEZ and MPA, our data warrant further investigation of their potential as novel therapy for CLL.Leukemia (2009) 23, 292–304; doi:10.1038/leu.2008.283; published online 16 October 2008 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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