Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism.
We describe several novel analogs of the seco-steroid 1,25(OH)2-vitamin D3[1,25(OH)2D3] and their effects on differentiation and proliferation of HL-60 human myeloid leukemic cells in vitro as well as their effects on calcium metabolism in vivo. The 1 alpha-25(OH)2-16ene-23yne-26,27F6-vitamin D3 is the most potent analog reported to date, having about 80-fold more activity than the reference 1,25(OH)2D3 for inhibition of proliferation and induction of differentiation of HL-60 cells. Also, this analog decreased RNA expression of MYC oncogene in HL-60 by 90% at 5 x 10(-10) mol/L. Intriguingly, intestinal calcium absorption and bone calcium mobilization mediated in vivo by 1 alpha-25(OH)2-16ene-23yne-26,27F6-D3 was found to be markedly (15-fold) less than that of 1,25(OH)2D3. In addition, 1 alpha-25(OH)2D3 bound to 1,25(OH)2D3 receptors of both HL-60 and intestine more avidly than did 1 alpha-25(OH)2-16ene-23yne-26,27F6-D3. This novel analog may open up new therapeutic strategies for several hematopoietic, skin, and bone abnormalities and may provide a new tool to understand how vitamin D3 seco-steroids induce cellular differentiation.
Zhou
J Y
JY
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
Norman
A W
AW
Akashi
M
M
Chen
D L
DL
Uskokovic
M R
MR
Aurrecoechea
J M
JM
Dauben
W G
WG
Okamura
W H
WH
Koeffler
H P
HP
D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002117:Calcitriol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D002117:Calcitriol; D002118:Calcium