Abstract
The seco-steroid hormone, 1 alpha, 25 dihydroxyvitamin D3 (1 alpha,25(OH)2D3) binds to a specific nuclear receptor that acts as a ligand-inducible transcription factor. The resulting genomic effects include partial arrest in G0/G1 of the cell cycle and induction of differentiation; these effects have been observed in various types of cancer. Recently, we produced enzymatically the natural 24-oxo metabolites of 1 alpha,25(OH)2D3 and two of its potent synthetic analogs (1 alpha,25-(OH)2-16-ene-D3 and 1 alpha,25-(OH)2-20-epi-D3) using a rat kidney perfusion system. We have found that the 24-oxo metabolites of both 1 alpha,25(OH)2D3 and its analogs have either the same or greater antiproliferative activity against various cancer cells as their parental compounds. Notably, two cell lines (DU-145 (prostate cancer) and MDA-MB-436 [breast cancer]) that were extremely resistant to the antiproliferative effects of vitamin D3 analogs displayed greater sensitivity towards the 24-oxo metabolite of the vitamin D3 analog. Similarly, the 24-oxo metabolites had the capacity to induce differentiation and apoptosis and to diminish the proportion of cells in S phase. Most interestingly, while the analog 1 alpha,25(OH)2-20-epi-D3 induced expression of BRCA1 in MCF-7 breast cancer cells; its 24-oxo metabolite dramatically suppressed BRAC1 expression. Thus, we have shown for the first time that the various biological activities produced by the hormone 1 alpha,25(OH)2D3 and some of its analogs may represent a combination of actions by the hormone 1 alpha,25(OH)2D3 and its natural 24-oxo metabolites.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / drug effects
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BRCA1 Protein / drug effects
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BRCA1 Protein / genetics
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BRCA1 Protein / metabolism
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Breast Neoplasms / drug therapy
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Cadherins / drug effects
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Cadherins / genetics
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Cadherins / metabolism
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Calcitriol / analogs & derivatives
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Calcitriol / metabolism
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Calcitriol / pharmacology
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Cell Cycle / drug effects
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Cell Cycle Proteins*
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Cell Division / drug effects
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Cholecalciferol / analogs & derivatives*
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Cholecalciferol / metabolism
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Cholecalciferol / pharmacology*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / drug effects
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Cyclins / genetics
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Cyclins / metabolism
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HL-60 Cells / drug effects
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Humans
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Male
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Microtubule-Associated Proteins / drug effects
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Neoplasms / drug therapy*
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Prostatic Neoplasms / drug therapy
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2*
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
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bcl-2-Associated X Protein
Substances
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BRCA1 Protein
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CDKN1A protein, human
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Cadherins
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Microtubule-Associated Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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1,25-dihydroxy-16-ene-vitamin D3
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Cyclin-Dependent Kinase Inhibitor p27
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Cholecalciferol
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1,25-dihydroxy-24-oxo-vitamin D3
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Calcitriol