TY - JOUR
T1 - 1α,25-Dihydroxy-16-Ene-23-Yne-26,27-Hexafluorocholecalciferol (Ro24-5531) Modulation of Insulin-Like Growth Factor-Binding Protein-3 and Induction of Differentiation and Growth Arrest in a Human Osteosarcoma Cell Line
AU - Velez-Yanguas, Maria C.
AU - Kalebic, Thea
AU - Maggi, Mario
AU - Kappel, Cynthia Chavez
AU - Letterio, John
AU - Uskokovic, Milan
AU - Helman, Lee J.
PY - 1996
Y1 - 1996
N2 - 1α,25-Dihydroxycholecalciferol [1,25-(OH)2D3] is a potent differentiating agent in a variety of tumor cell lines. However, the induction of severe hypercalcemia has limited its clinical use. Several analogs have been synthesized that retain the antiproliferative differentiating effects of 1,25-(OH)2DM3, but do not have the calcitropic effect of the parent compound. One such analog, 1α,25(OH)2-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), can induce differentiation in HL-60 cells and does not induce hypercalcemia in animal models. We, therefore, evaluated the effect of Ro24-5531 on a human osteosarcoma cell line, MG-63. Compared with 1,25-(OH)2D3, the analog Ro24-5531 is 10-100 times more potent as an inhibitor of MG-63 cell proliferation, as determined by [3H]thymidine incorporation and/or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The inhibition in cell growth is accompanied by a decrease in the expression of p34cdc2 (>4-fold), a protein critically involved in cell cycle regulation. Ro24-5531 treatment of MG-63, at a concentration of 10-8 mol/L, induced expression of the bone differentiation markers biglycan and osteocalcin, as determined by Northern analysis. These data suggest that Ro24-5531 treatment induces growth arrest coupled with differentiation. To begin to evaluate the mechanisms by which Ro24-5531 may exert an effect, we evaluated the effect of Ro24-5531 on components of the insulin-like growth factor I (IGF-I) signaling pathway, an important regulator of normal bone growth and differentiation. The expression of IGF-binding protein (IGFBP), IGFBP-3 messenger ribonucleic acid, and protein levels are increased 20-fold after 72 h of treatment with Ro24-5531 and are associated with a marked increase in detectable binding of ligand to binding protein, as measured by RRA. These data suggest an association between Ro24-5531-induced growth arrest and increased expression of IGFBP-3.
AB - 1α,25-Dihydroxycholecalciferol [1,25-(OH)2D3] is a potent differentiating agent in a variety of tumor cell lines. However, the induction of severe hypercalcemia has limited its clinical use. Several analogs have been synthesized that retain the antiproliferative differentiating effects of 1,25-(OH)2DM3, but do not have the calcitropic effect of the parent compound. One such analog, 1α,25(OH)2-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), can induce differentiation in HL-60 cells and does not induce hypercalcemia in animal models. We, therefore, evaluated the effect of Ro24-5531 on a human osteosarcoma cell line, MG-63. Compared with 1,25-(OH)2D3, the analog Ro24-5531 is 10-100 times more potent as an inhibitor of MG-63 cell proliferation, as determined by [3H]thymidine incorporation and/or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The inhibition in cell growth is accompanied by a decrease in the expression of p34cdc2 (>4-fold), a protein critically involved in cell cycle regulation. Ro24-5531 treatment of MG-63, at a concentration of 10-8 mol/L, induced expression of the bone differentiation markers biglycan and osteocalcin, as determined by Northern analysis. These data suggest that Ro24-5531 treatment induces growth arrest coupled with differentiation. To begin to evaluate the mechanisms by which Ro24-5531 may exert an effect, we evaluated the effect of Ro24-5531 on components of the insulin-like growth factor I (IGF-I) signaling pathway, an important regulator of normal bone growth and differentiation. The expression of IGF-binding protein (IGFBP), IGFBP-3 messenger ribonucleic acid, and protein levels are increased 20-fold after 72 h of treatment with Ro24-5531 and are associated with a marked increase in detectable binding of ligand to binding protein, as measured by RRA. These data suggest an association between Ro24-5531-induced growth arrest and increased expression of IGFBP-3.
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U2 - 10.1210/jcem.81.1.8550801
DO - 10.1210/jcem.81.1.8550801
M3 - Article
C2 - 8550801
AN - SCOPUS:0029670649
SN - 0021-972X
VL - 81
SP - 93
EP - 99
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 1
ER -