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

Abstract

1α,25-Dihydroxyvitamin D3 [1α,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 1α,25 (OH) 2D3 have clearly demonstrated that the A-ring analogs that contain 1α-hydroxy or 3β-hydroxy group are potent inducers of HL-60 cell differentiation. In contrast, the A-ring analogs that contain 1β-hydroxy or 3α-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 1α,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 1α,25 (OH) 2D3, and the proteins responsible for the regulation of cell cycle and mitochondrial membrane potential are the major targets of 1α,25 (OH) 2D3 analogs. These findings provide useful information not only for structure-function studies of 1α,25 (OH) 2D3 analogs but also for the development of therapeutic agents for the treatment of cancer. © 2002 The Pharmaceutical Society of Japan.