Inhibition of bcl-2 with antisense oligonucleotides induces apoptosis and increases the sensitivity of AML blasts to Ara-C

Leukemia. 1995 Jan;9(1):131-8.

Abstract

We have previously shown that blasts from acute myeloid leukaemia (AML) patients which grow autonomously in culture have high bcl-2 expression which in turn has been linked to a poor clinical response to chemotherapy. The bcl-2 protein promotes cell survival by preventing the onset of apoptosis or programmed cell death following growth-factor deprivation. Bcl-2 has also been shown to be responsible for chemo-resistance in human leukaemic cell lines. Here we have investigated the role of bcl-2 expression in mediating resistance to apoptosis induced by cytosine arabinoside in vitro. The blasts from 17 AML patients exhibiting autonomous growth in a blast cell colony assay and expressing high levels of bcl-2 protein were studied. Incubation of the blasts with antisense oligonucleotides directed against bcl-2 mRNA resulted in a significant decrease in expression of the bcl-2 protein in seven of the 17 samples. In these seven cases the decreased expression of bcl-2 was accompanied by increased apoptosis and the susceptibility of the blasts to apoptosis induced by Ara-C was increased in the presence of bcl-2 antisense. As a high level of bcl-2 defines a group of AML patients who exhibit a poor response to chemotherapy, the demonstration that chemosensitivity of a significant proportion of these patients can be increased by bcl-2 antisense suggests this approach may have clinical potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Base Sequence
  • Cytarabine / pharmacology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Humans
  • Leukemia, Myeloid, Acute / pathology*
  • Molecular Sequence Data
  • Oligonucleotides, Antisense / pharmacology*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Cells, Cultured

Substances

  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Cytarabine
  • Granulocyte-Macrophage Colony-Stimulating Factor