Antisense-mediated suppression of Bcl-2 highlights its pivotal role in failed apoptosis in B-cell chronic lymphocytic leukaemia

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Abstract
Although advances have been made in the development of more effective treatment modalities, B‐cell chronic lymphocytic leukaemia (B‐CLL) remains incurable due to the development of drug resistance. Defective programmed cell death mechanisms rather than dysregulation of cell cycle appears to predominate in B‐CLL and it is likely that a failure to initiate apoptosis contributes to chemoresistance. Most B‐CLL cells contain high levels of the anti‐apoptotic protein Bcl‐2 and high Bcl‐2/Bax ratios have been associated with in vitro resistance to cytotoxic agents. In this study we evaluated the cellular responses to a Bcl‐2 antisense oligonucleotide in terms of Bcl‐2 mRNA and protein expression and the induction of apoptosis. The antisense molecule induced a specific reduction in Bcl‐2 mRNA and protein expression over the 48 h culture period and was associated with increased apoptosis. The study indicates that Bcl‐2 protein is central to the mediation of resistance to apoptosis in B‐CLL. Therefore Bcl‐2 antisense oligonucleotides might be useful in the treatment of B‐CLL.