Anti-endothelial properties of 1,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of calcitriol*1

Abstract

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.