Subject(s)
Antineoplastic Agents/therapeutic use , Gene Expression Regulation, Neoplastic , Immunoglobulin Heavy Chains/genetics , Integrin alpha4/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Receptors, CXCR4/genetics , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Antibodies, Monoclonal, Humanized/therapeutic use , Benzylamines , Chemokine CXCL12/genetics , Chemokine CXCL12/metabolism , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Cyclams , Genetic Heterogeneity , Heterocyclic Compounds/therapeutic use , Humans , Immunoglobulin Heavy Chains/metabolism , Integrin alpha4/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Mutation , Natalizumab , Piperidines , Prognosis , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Quinazolinones/therapeutic use , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolism , Signal Transduction , Survival AnalysisABSTRACT
OBJECTIVES: Non-steroidal anti-inflammatory drugs have been shown to induce apoptosis in primary B-cell chronic lymphocytic leukaemia (CLL) cells, but the molecular mechanisms that underpin this observation have not been fully elucidated. Here, we have analysed the effect two novel aspirin analogues, 2-hydroxy benzoate zinc (2HBZ) and 4-hydroxy benzoate zinc (4HBZ), on primary CLL samples. MATERIALS AND METHODS: Cytotoxic effects of 2HBZ and 4HBZ were analysed in primary CLL cells derived from 52 patients, and normal B- and T-lymphocytes. Mechanisms of action of these agents were also elucidated. RESULTS: Both analogues induced apoptosis in a dose-dependent and time-dependent manner. Apoptosis was associated with activation of caspase-3 that could be partially abrogated by the caspase-9 inhibitor (Z-LEHD.fmk). Importantly, both agents demonstrated preferential cytotoxicity in CLL cells when compared to normal B- and T-lymphocytes. In terms of their molecular mechanisms of action, 4HBZ and 2HBZ inhibited COX-2 transcription and protein expression and this was associated with upstream inhibition of transcription factor Rel A. Co-culture of CLL cells with CD40 ligand-expressing mouse fibroblasts significantly increased COX-2 expression and inhibited spontaneous apoptosis. Importantly, the most potent analogue, 4HBZ, overcame pro-survival effects of the co-culture system and significantly repressed COX-2. Finally, elevated COX-2 expression was associated with poor prognostic subsets and increased sensitivity to 4HBZ. CONCLUSIONS: Our results demonstrate therapeutic potential of 4HBZ and are consistent with a mechanism involving suppression of Rel A nuclear translocation and inhibition of COX-2 transcription.