Back to Search
Start Over
[Analysis of molecular mechanism of cancer cell differentiation and apoptosis induced by vitamin D3 analogs on the basis of molecular recognition of vitamin D receptor ligand binding domain].
- Source :
-
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan [Yakugaku Zasshi] 2002 Oct; Vol. 122 (10), pp. 781-91. - Publication Year :
- 2002
-
Abstract
- 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.
- Subjects :
- Cholecalciferol analogs & derivatives
Humans
Ligands
Receptors, Calcitriol chemistry
Stereoisomerism
Structure-Activity Relationship
Tumor Cells, Cultured
Apoptosis drug effects
Cell Differentiation drug effects
Cholecalciferol pharmacology
Neoplasms pathology
Receptors, Calcitriol physiology
Subjects
Details
- Language :
- Japanese
- ISSN :
- 0031-6903
- Volume :
- 122
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
- Publication Type :
- Academic Journal
- Accession number :
- 12400159
- Full Text :
- https://doi.org/10.1248/yakushi.122.781