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

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.