Paul Furigay1, Narasimha Swamy. 1. Department of Pediatrics, Women and Infants' Hospital, Brown University, 101 Dudley Street, Providence, RI 02905, USA.
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.
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.
Authors: E Vanoirbeek; A Krishnan; G Eelen; L Verlinden; R Bouillon; D Feldman; A Verstuyf Journal: Best Pract Res Clin Endocrinol Metab Date: 2011-08 Impact factor: 4.690
Authors: G Damera; H W Fogle; P Lim; E A Goncharova; H Zhao; A Banerjee; O Tliba; V P Krymskaya; R A Panettieri Journal: Br J Pharmacol Date: 2009-10-08 Impact factor: 8.739