Two novel aspirin analogues show selective cytotoxicity in primary chronic lymphocytic leukaemia cells that is associated with dual inhibition of Rel A and COX-2
2011
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 prosurvival
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.
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