The noncalcemic vitamin D analogs EB1089 and 22-oxacalcitriol suppress serum-induced parathyroid hormone-related peptide gene expression in a lung cancer cell line

PTH-related peptide (PTHrP) mediates the syndrome of humoral hypercalcemia of malignancy, a frequent complication of squamous cell carcinomas of the lung. This study was undertaken to determine whether 1,25- dihydroxyvitamin D₃ [1,25-(OH)₂D₃] and two nonhypercalcemic analogs, EB1089 and 22-oxa-1,25-(OH)₂D₃ (22-oxacalcitriol), suppress serum- and epidermal growth factor (EGF)-induced PTHrP gene expression in a human tung squamous cancer cell line, NCI H520. PTHrP expression was up-regulated by serum and EGF in a concentration- and time-dependent manner. Nuclear run-on analysis showed that this induction was mediated via a transcriptional mechanism, and that sequences within promoter 1 were responsible. All three vitamin D₃ compounds decreased both basal and serum- and EGF-induced steady state PTHrP messenger RNA and secreted peptide levels. These effects were again mediated via a transcriptional mechanism through sequences within promoter 1. All three vitamin D₃ compounds also decreased the proliferation of NCI H520 cells in a concentration- and time-dependent manner. 1,25- (OH)₂D₃ is hypercalcemic in vivo. However, the noncalcemic analogs EB 1089 and 22-oxa- 1,25-(OH)₂D₃ have therapeutic potential, as they suppress not only the basal but also the growth factor-stimulated levels of PTHrP in a cancer cell line associated with hypercalcemia.