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

Pepper, Christopher John, Mahdi, J. G., Buggins, A. G. S., Hewamana, Saman, Walsby, Elisabeth Jane ORCID: https://orcid.org/0000-0001-8523-5017, Mahdi, Eamon, Al-Haza'a, A., Mahdi, Ali J., Lin, Thet Thet, Pearce, Laurence, Morgan, Liam David ORCID: https://orcid.org/0000-0002-7571-6025, Bowen, Ivor D., Brennan, Paul ORCID: https://orcid.org/0000-0001-8792-0499 and Fegan, Christopher Daniel ORCID: https://orcid.org/0000-0001-9685-0621 2011. 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. Cell Proliferation 44 (4) , pp. 380-390. 10.1111/j.1365-2184.2011.00760.x

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Wiley
ISSN:	0960-7722
Last Modified:	03 Feb 2023 02:05
URI:	https://orca.cardiff.ac.uk/id/eprint/26241

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