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1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25 (OH)2D3] has antiproliferative, differentiation and apoptosis-inducing effects on many malignant cells. These properties have raised the possibility of its use as a therapeutic agent in cancer. Our recent studies using stereoisomers of the A-ring of monohydroxylated 19-nor or 2-methyl substituted 1 alpha,25 (OH)2D3 have clearly demonstrated that the A-ring analogs that contain 1 alpha-hydroxy or 3 beta-hydroxy group are potent inducers of HL-60 cell differentiation. In contrast, the A-ring analogs that contain 1 beta-hydroxy or 3 alpha-hydroxy group are potent stimulators of HL-60 cell apoptosis. It was interesting to note that the analogs could induce differentiation or apoptosis of HL-60 cells on the basis of the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring. To further elucidate the possible roles of both the hydroxy groups in regulating cell differentiation and apoptosis, we have synthesized all possible diastereomers of the A-ring of 1 alpha,25 (OH)2D3 and examined their molecular mechanism of differentiation and apoptosis-inducing actions of HL-60 cells in vitro. This study shows that differentiation and apoptosis of HL-60 cells are strictly controlled by the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring of 1 alpha,25 (OH)2D3, and the proteins responsible for the regulation of cell cycle and mitochondrial membrane potential are the major targets of 1 alpha,25 (OH)2D3 analogs. These findings provide useful information not only for structure-function studies of 1 alpha,25 (OH)2D3 analogs but also for the development of therapeutic agents for the treatment of cancer.

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Analysis of Molecular Mechanism of Cancer Cell Differentiation and Apoptosis Induced by Vitamin D&lt;sub&gt;3&lt;/sub&gt; Analogs on the Basis of Molecular Recognition of Vitamin D Receptor Ligand Binding Domain