Anti-endothelial properties of 1,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of calcitriol.
BACKGROUND
Calcitriol [1,25-(OH)(2)D(3)] is a strong anti-proliferative agent both in vitro and in vivo. Earlier studies have established that calcitriol inhibits the growth factor-stimulated proliferation of endothelial cells (EC) and angiogenesis. However, the lethal calcemic side effects of calcitriol prohibit its use as a therapeutic agent. Several analogs of vitamin D have been developed to minimize these calcemic side effects. 1,25-dihydroxy-3-epi-vitamin D(3) (3-epiD(3)), a naturally formed vitamin D metabolite is one such analog.


OBJECTIVE
To demonstrate that 3-epiD(3), a calcitriol analog, inhibits endothelial cell proliferation and induces apoptosis.


RESULTS
Treatment of EC with 3-epiD(3) showed 60% inhibition (P < 0.006) of proliferation. Cell viability assays corroborated these results. Pro-apoptotic caspase-3 activity was increased fourfold (P < 0.01) in 3-epiD(3)-treated cells over controls. 3-epiD(3) induced apoptosis in EC as shown by genomic DNA fragmentation. Cell cycle analysis of 3-epiD(3)-treated EC revealed a G0/G1 arrest.


CONCLUSIONS
3-epiD(3), a low-calcemic, natural analog of calcitriol, inhibits EC proliferation by causing a G0/G1 arrest and induces apoptosis more effectively than 1,25-(OH)(2)D(3). These results suggest that 3-epiD(3) is a potent inhibitor of EC growth.
Furigay
Paul
P
Department of Pediatrics, Women and Infants' Hospital, Brown University, 101 Dudley Street, Providence, RI 02905, USA.
Swamy
Narasimha
N
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans
D002762:Cholecalciferol; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C025168:previtamin D(3)