1,25-Dihydroxyvitamin D3 and its analogues inhibit acute myelogenous leukemia progenitor proliferation by suppressing interleukin-1β production

We hypothesized that 1,25-dihydroxyvitamin D3 (1,25D₃) and its analogues may inhibit acute myelogenous leukemia (AML) proliferation by interrupting IL-1β-mediated growth-stimulatory signals. The incubation of the IL-1β-responsive AML cell line OCIM2 with 10 nM 1,25D₃ reduced growth 80% in liquid culture, and a 100-1000-fold lower concentration of 20-epi analogues (MC1288 and MC1301) was sufficient to achieve similar growth inhibition. The growth inhibition was associated with a rapid but transient downregulation of IL-1β and IL-1β-converting enzyme (ICE) mRNAs in 1,25D₃- and 20-epi analogue-treated cells, and the 20-epi analogue was more effective than 1,25D₃ in repressing ICE expression. An examination of long- term changes in the levels of mature IL-1β and its precursor revealed that 24-h incubation of OCIM2 with either 1,25D₃ or its 20-epi analogues abolished the production of mature IL-1β. The effect of 1,25D₃ and its analogues on growth of fresh bone marrow cells from seven AML patients was tested by a clonogenic assay. Growth inhibition of 60% was reached in only one of seven 1,25D₃-treated samples, but all seven samples were inhibited 60-90% by the 20-epi analogue MC1301. Growth inhibition by 1,25D₃ and the analogue was reversible by addition of IL-1β. These results suggest that 1,25D₃ and its 20-epi analogues interrupt IL-1β autocrine growth regulation by inhibiting IL-1β production and processing but not the response to IL- 1β.