The noncalcemic vitamin D analogues EB1089 and 22-oxacalcitriol interact with the vitamin D receptor and suppress parathyroid hormone-related peptide gene expression.
Humoral hypercalcemia of malignancy, a frequent complication of squamous cell carcinomas of the lung, is mediated by the parathyroid hormone-related peptide (PTHrP). This study was undertaken to determine whether 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and two nonhypercalcemic analogues. EB1089 and 22-oxa-1,25(OH)(2)D(3) (OCT), suppress PTHrP gene expression in a human lung squamous cancer cell line, NCI H520. All three compounds (1) decreased steady-state PTHrP mRNA and secreted peptide levels via a transcriptional mechanism; (2) modulated promoter activity of 1,25(OH)(2)D(3)-responsive DNA sequences; and (3) activated the vitamin D receptor (VDR) both in vitro and in vivo. Thus, EB1089 and OCT inhibit PTHrP gene expression in NCI H520 cells and modulate gene expression through the same mechanism as 1,25(OH)(2)D(3), namely, activation of the VDR. 1,25(OH)(2)D(3) is hypercalcemic in vivo. However, the noncalcemic analogues EB1089 and OCT have a therapeutic potential through suppression of PTHrP gene transcription.
Falzon
M
M
Department of Pharmacology and Toxicology, and Sealy Center for Molecular Science, The University of Texas Medical Branch, Galveston 77555, USA.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002117:Calcitriol; C051883:maxacalcitol; C078903:seocalcitol