1 alpha,25-dihydroxyvitamin D-3-26,23-lactone analogs antagonize differentiation of human leukemia cells (HL-60 cells) but not of human acute promyelocytic leukemia cells (NB4 cells)

We examined the effects of two novel 1 alpha,25-dihydroxyvitamin D-3-26,23- lactone (1 alpha,25-(OH)(2)D-3-26,23-lactone) analogs on 1 alpha,25(OH)(2)D -3-induced differentiation of human leukemia HL-60 cells thought to be medi ated by the genomic action of 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25-( OH)(2)D-3) and of acute promyelocytic leukemia NB4 cells thought to be medi ated by non-genomic actions of 1 alpha,25-(OH)(2)D-3. We found that the 1 a lpha,25-(OH)(2)D-3-26,23-lactone analogs, (23S)-25-dehydro-1 alpha-hydroxyi tamin D-3-26,23-lactone (TEI-9647) and (23R)-25-dehyro-1 alpha-hydroxyvitam in D-3-26,23-lactone (TEI-9648), inhibited differentiation of HL-60 cells i nduced by 1 alpha,25-(OH)(2)D-3, However, 1 beta-hydroxyl diastereomers of these analogs, i,e, (23S)-25-dehydro-1 beta-hydroxyvitamin D-3-26,23-lacton e (1 beta-TEI-9647) and (23R)-25-dehydro-1 beta-hydroxyvitamin D-3-26,23-la ctone (1 beta-TEI-9648), did not inhibit differentiation of HL-60 cells cau sed by 1 alpha,25-(OH)(2)D-3. A separate study showed that the nuclear vita min a receptor (VDR) binding affinities of the 1 alpha-hydroxyl diastereome rs were about 200 and 90 times weaker than that of la-hydroxyl diastereomer s, respectively. Moreover, none of these lactone analogs inhibited NB4 cell differentiation induced by 1 alpha,25-(OH)(2)D-3. In contrast, 1 beta,25-d ihydroxyvitamin D-3 (1 beta,25-(OH)(2)D-3) and 1 beta,24R-dihydroxyvitamin D-3 (1 beta,24R-(OH)(2)D-3) inhibited NB4 cell. differentiation but not HL- 60 cell differentiation. Collectively, the results suggested that 1-hydroxy l lactone analogs, i,e, TEI-9647 and TEI-9648, are antagonists of 1 alpha,2 5-(OH)(2)D-3, specifically for the nuclear VDR-mediated genomic actions, bu t not for non-genomic actions. (C) 1999 Federation of European Biochemical Societies.