Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins

The antiapoptotic proteins, Bcl-2 and Bcl-X-L, are expressed in most cases of acute myeloid leukemia (AML) and may contribute to drug resistance in AM L, We tested the hypothesis that down-regulation of Bcl-2 alone by antisens e 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 A ML samples. Downregulation 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 cytoto xicity in both cell lines. Incubation of primary AML blasts with Bcl-2-AS d ecreased Bcl-2 expression in CD34(+) blast cells after induction of apoptos is and enhancement of ara-C cytotoxicity in 11 of 19 primary AML samples. I n 8 samples in which Bcl-2-AS did not induce apoptosis, baseline Bcl-2 leve ls were found to be strikingly high, The expression of other antiapoptotic proteins (Bcl-X-L, Bag-1,A1, and Mcl-1) did not prevent Bcl-2-AS-induced ap optosis, Bcl-2-AS also inhibited colony formation of AML progenitor cells. Low concentrations of Bcl-2-AS induced significant increases in S-phase cel ls (P = .04), Results establish Bcl-2 as a critical target for AS strategie s in AML in which the baseline levels predict response to Bcl-2-AS, Bcl-2 e xerts both antiapoptotic and antiproliferative functions in AML, Because ea rly normal hematopoietic stem cells do not express Bcl-2, Bcl-2-AS therapy should be highly selective for AML cells. (C) 2000 by The American Society of Hematology.