Interaction of Two Novel 14-Epivitamin D3 Analogs with Vitamin D3 Receptor-Retinoid X Receptor Heterodimers on Vitamin D3 Responsive Elements

Abstract

ABSTRACT

Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system

“…The active vitamin D metabolite, 1α, 25-dihydroxyvitamin D 3 (1,25D 3 ), has shown antitumor activities in vitro and in vivo in a number of cancer types. 1 Hypercalcemia may be the dose-limiting factor for the application of 1,25D 3 in the clinic, particularly when continuous dosing schedules are employed.…”

“…1 Hypercalcemia may be the dose-limiting factor for the application of 1,25D 3 in the clinic, particularly when continuous dosing schedules are employed. 1 Therefore, efforts have been made to develop analogs of 1,25D 3 with a dissociation of antiproliferative and calcemic effects. 1 1,25D 3 and its analogs exert a genomic action by binding to the intracellular vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor (RXR).…”

“…1 Therefore, efforts have been made to develop analogs of 1,25D 3 with a dissociation of antiproliferative and calcemic effects. 1 1,25D 3 and its analogs exert a genomic action by binding to the intracellular vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor (RXR). The heterodimer subsequently recruits coactivators and binds to vitamin D response elements epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D 3 (1,25D 3 ) has broad spectrum antitumor activity.…”

“…Hypercalcemia has often been suggested to limit the clinical application of these data. the 14-epi-analog of 1,25D 3 , inecalcitol [19-nor-14-epi-23-yne-1,25-(oH) 2 D 3 ; tX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system.…”

“…We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D 3 , inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC 50 value 30 times lower than that of 1,25D 3 .…”