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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3929-3938
Liposomal Bcl-2 antisense oligonucleotides enhance proliferation,
sensitize acute myeloid leukemia to cytosine-arabinoside, and
induce apoptosis independent of other antiapoptotic proteins
Marina Konopleva,
Ana M. Tari,
Zeev Estrov,
David Harris,
Zhong Xie,
Shourong Zhao,
Gabriel López-Berestein, and
Michael Andreeff
From The University of Texas M. D. Anderson Cancer Center, Houston,
TX.
The antiapoptotic proteins, Bcl-2 and Bcl-XL, are
expressed in most cases of acute myeloid leukemia (AML) and may
contribute to drug resistance in AML. We tested the hypothesis that
down-regulation of Bcl-2 alone by antisense oligodeoxynucleotides
(Bcl-2-AS) induces apoptosis, even in the presence of other
antiapoptotic genes. We tested Bcl-2-AS in myeloid leukemic HL-60
cells, in Bcl-2 and Bcl-XL overexpressing HL-60-DOX cells,
and in primary AML samples. Down-regulation of Bcl-2 by Bcl-2-AS
reduced the viability of HL-60 cells and, less effectively, HL-60-DOX
cells and increased ara-C cytotoxicity in both cell lines. Incubation
of primary AML blasts with Bcl-2-AS decreased Bcl-2 expression in
CD34+ blast cells after induction of apoptosis and
enhancement of ara-C cytotoxicity in 11 of 19 primary AML samples. In 8 samples in which Bcl-2-AS did not induce apoptosis, baseline Bcl-2
levels were found to be strikingly high. The expression of other
antiapoptotic proteins (Bcl-XL, Bag-1, A1, and Mcl-1) did
not prevent Bcl-2-AS-induced apoptosis. Bcl-2-AS also inhibited colony
formation of AML progenitor cells. Low concentrations of Bcl-2-AS
induced significant increases in S-phase cells (P = .04).
Results establish Bcl-2 as a critical target for AS strategies in AML
in which the baseline levels predict response to Bcl-2-AS. Bcl-2 exerts
both antiapoptotic and antiproliferative functions in AML. Because
early normal hematopoietic stem cells do not express Bcl-2, Bcl-2-AS
therapy should be highly selective for AML cells.
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