ENHANCEMENT BY ANTISENSE OLIGONUCLEOTIDES TO NF-KB OF THE DIFFERENTIATION OF HL-60 PROMYELOCYTIC LEUKEMIA-CELLS INDUCED BY VITAMIN-D-3

We have demonstrated previously that a phosphorothioate antisense olig onucleotide to the p65 subunit of the inducible transcription factor N F-kB produced rapid changes in the expression of leukocyte integrin CD 11b (Mo 1) and in the adhesion of dimethylsulfoxide (DMSO)-differentia ted HL-60 cells stimulated by 12-O-tetradecanoylphorbol 13-acetate. We have also shown that a variety of agents which inhibit NF-kB, includi ng vitamin E and related antioxidants, curcumin and several nonsteroid al anti-inflammatory agents, significantly enhanced the differentiatio n of HL-60 leukemia cells when combined with low levels of 1,25-dihydr oxyvitamin D-3 (vitamin D-3). To provide further evidence that interfe rence with the activation of NF-kB affects the maturation of HL-60 leu kemia cells by creating an environment conducive to terminal different iation, we measured the effects of phosphorothioate antisense oligonuc leotides to the various subunits of NF-kB on the differentiation of HL -60 cells produced by low levels of vitamin D-3. When used alone these oligonucleotides had no significant effect on the differentiation of HL-60 cells. However, the antisense oligomer to the Rel A subunit of N F-kB markedly increased the extent of differentiation produced by low levels of vitamin D-3. An enhancement of the differentiation of HL-60 cells induced by vitamin D-3 was also obtained by several transcriptio n factor decoys designed to mimic the consensus sequences of genes act ivated by Rel A. The findings provide additional support for the conce pt that inhibition of the activation of NF-kB may be involved in regul ating the entry of promyelocytic leukemia cells into a differentiation pathway. (C) 1998 Elsevier Science Ireland Ltd.