1,25-Dihydroxyvitamin D3 and its analogues inhibit acute myelogenous leukemia progenitor proliferation by suppressing interleukin-1beta production.
We hypothesized that 1,25-dihydroxyvitamin D3 (1,25D3) and its analogues may inhibit acute myelogenous leukemia (AML) proliferation by interrupting IL-1beta-mediated growth-stimulatory signals. The incubation of the IL-1beta- 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-1beta and IL-1beta-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-1beta 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-1beta. 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-1beta. These results suggest that 1,25D3 and its 20-epi analogues interrupt IL-1beta autocrine growth regulation by inhibiting IL-1beta production and processing but not the response to IL-1beta.
Peleg
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Department of Medical Specialties, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Qiu
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Reddy
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Harris
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Van
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Estey
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EH
Talpaz
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Estrov
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D000970:Antineoplastic Agents; D019898:Autocrine Communication; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007375:Interleukin-1; C090061:CB 966; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D002117:Calcitriol