1α,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)

Abstract

We examined the effects of two novel 1α,25-dihydroxyvitamin D 3-26,23-lactone (1α,25-(OH) 2D 3-26,23-lactone) analogs on 1α,25(OH) 2D 3-induced differentiation of human leukemia HL-60 cells thought to be mediated by the genomic action of 1α,25-dihydroxyvitamin D 3 (1α,25-(OH) 2D 3) and of acute promyelocytic leukemia NB4 cells thought to be mediated by non-genomic actions of 1α,25-(OH) 2D 3. We found that the 1α,25-(OH) 2D 3-26,23-lactone analogs, (23 S)-25-dehydro-1α-hydroxyvitamin D 3-26,23-lactone (TEI-9647) and (23 R)-25-dehydro-1α-hydroxyvitamin D 3-26,23-lactone (TEI-9648), inhibited differentiation of HL-60 cells induced by 1α,25-(OH) 2D 3. However, 1β-hydroxyl diastereomers of these analogs, i.e. (23 S)-25-dehydro-1β-hydroxyvitamin D 3-26,23-lactone (1β-TEI-9647) and (23 R)-25-dehydro-1β-hydroxyvitamin D 3-26,23-lactone (1β-TEI-9648), did not inhibit differentiation of HL-60 cells caused by 1α,25-(OH) 2D 3. A separate study showed that the nuclear vitamin D receptor (VDR) binding affinities of the 1-hydroxyl diastereomers were about 200 and 90 times weaker than that of 1α-hydroxyl diastereomers, respectively. Moreover, none of these lactone analogs inhibited NB4 cell differentiation induced by 1α,25-(OH) 2D 3. In contrast, 1β,25-dihydroxyvitamin D 3 (1β,25-(OH) 2D 3) and 1β,24 R-dihydroxyvitamin D 3 (1β,24 R-(OH) 2D 3) inhibited NB4 cell differentiation but not HL-60 cell differentiation. Collectively, the results suggested that 1-hydroxyl lactone analogs, i.e. TEI-9647 and TEI-9648, are antagonists of 1α,25-(OH) 2D 3, specifically for the nuclear VDR-mediated genomic actions, but not for non-genomic actions.