title: Structure-specific control of differentiation and apoptosis of human promyelocytic leukemia (HL-60) cells by A-ring diastereomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) and its 20-epimer.
abstract: 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) has been shown to modulate not only proliferation and differentiation but also apoptosis of malignant cells, indicating that it would be useful for the treatment of hyperproliferative diseases such as cancer and psoriasis. Little information is available concerning structural motifs of the 1alpha,25(OH)(2)D(3) molecule responsible for modulation of differentiation and apoptosis. We synthesized all possible A-ring diastereomers of the 2-methyl-1alpha,25(OH)(2)D(3) and its 20-epimer and evaluated their biological activities in human promyelocytic leukemia (HL-60) cells. Surprisingly, the potent analogues could be clearly divided into two groups: (i) those bearing the 1alpha- and 3beta-hydroxyl groups on the A-ring were potent inducers of differentiation and growth inhibitors of HL-60 cells and (ii) those bearing the 1beta-hydroxyl group together with either 3alpha- or 3beta-hydroxyl groups on the A-ring were potent stimulators of apoptosis in these cells. We have clearly identified for the first time the structural motifs on the basis of the stereochemistry of both hydroxyl groups at positions 1 and 3 of the A-ring of the 1alpha,25(OH)(2)D(3) molecule responsible for the induction of differentiation and apoptosis of HL-60 cells. These findings provide useful information not only for structure-function studies of 1alpha,25(OH)(2)D(3) analogues but also for the development of therapeutic agents for the treatment of leukemia and other cancers.
authors: Department of Hygienic Sciences, Kobe Pharmaceutical University, 658-8558, Kobe, Japan.
authors: K
authors: K
authors: Nakagawa
authors: M
authors: M
authors: Kurobe
authors: K
authors: K
authors: Konno
authors: T
authors: T
authors: Fujishima
authors: H
authors: H
authors: Takayama
authors: T
authors: T
authors: Okano
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D018922:HL-60 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D015473:Leukemia, Promyelocytic, Acute; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C116441:2-methyl-1,25-dihydroxyvitamin D3; D016177:Macrophage-1 Antigen; D014807:Vitamin D