Antisense-mediated suppression of Bcl-2 highlights its pivotal role in failed apoptosis in B-cell chronic lymphocytic leukaemia.
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.
Pepper
C
C
Department of Haematology, Llandough Hospital, Penarth, South Glamorgan, London.
Thomas
A
A
Hoy
T
T
Cotter
F
F
Bentley
P
P
D017209:Apoptosis / Q000235:genetics*; D019254:Genes, bcl-2 / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein