The noncalcemic vitamin D analogues EB1089 and 22-oxacalcitriol interact with the vitamin D receptor and suppress parathyroid hormone-related peptide gene expression

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Abstract

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 D3 [1,25(OH)2D3] and two nonhypercalcemic analogues, EB1O89 and 22-oxa-1,25(OH)2D3 (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(0H)2D3-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)2D3, namely, activation of the VDR. 1,25(OH)2D3 is hypercalcemic in vivo. However, the noncalcemic analogues EB1089 and OCT have a therapeutic potential through suppression of PTHrP gene transcription.

Original languageEnglish (US)
Pages (from-to)99-108
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume127
Issue number1
DOIs
StatePublished - Mar 14 1997

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Keywords

  • 1,25-dihydroxyvitamin D
  • 22-oxacalcitriol
  • D
  • EB1089
  • Parathyroid hormone-related peptide
  • Transcription
  • Vitamin D receptor

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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