Human Bladder as a Novel Target for Vitamin D Receptor Ligands

Abstract

Human prostate is now considered a target for vitamin D receptor (VDR) ligands, such as BXL-628. Because BXL-628 inhibited prostate growth without interfering with androgen signaling, it represents a new option for benign prostate hyperplasia (BPH) therapy. However, BPH symptoms are related not only to prostate size, but also to compensatory bladder hypertrophy and eventual overactivity. We now report that human bladder expresses VDR (determined by real-time PCR immunohistochemistry and Western blot) and responds to VDR agonists, such as the natural ligand, calcitriol, and its synthetic and less hypercalcemic derivative, BXL-628. Experiments were conducted with stromal cells derived from human bladder neck obtained at surgery from BPH patients. BXL-628 counteracted keratinocyte growth factor (KGF) and androgen-induced cell proliferation and stimulated apoptosis with a parallel reduced expression of the survival oncoprotein Bcl-2. Prolonged serum starvation time-dependently pushed bladder stromal cells to express activated myofibroblast markers, such as desmin and smoothelin, without changing other contractile-related proteins and intermediate filaments, such as vimentin. Chronic exposure to BXL-628 prevented starvation-induced cell phenotype modification. Because hypertrophy and starvation-induced bladder remodeling are supposed to underlie bladder overactivity, it is possible that BXL-628 might be helpful in reducing not only cumbersome symptoms related to prostate overgrowth, but also those related to bladder irritation.

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

“…Treatment of EAP by a VDR agonist represents a novel application for these hormone-like agents. The VDR is not only expressed by cells from classic target tissues as bone, bowel, and kidney but also in several others, including those derived from the urogenital sinus, such as prostate (49) and bladder (50). Interestingly, epithelial prostate cells express 1␣-hydroxylase, which is required for 1,25-dihydroxyvitamin D 3 synthesis (51).…”

Rho-kinase and effects of Rho-kinase inhibition on the lower urinary tract

“…67 Bladder smooth muscle cells are known to express vitamin D receptors. 68 Morelli et al 69 studied the effects of BXL-628, a calcitriol analog shown to decrease prostate growth in preclinical and clinical studies, on Rho-kinase signaling in rat and human bladder. They found that carbachol responsiveness was delayed and Rho-kinase activity reduced by BXL-628 treatment because of impaired RhoA membrane translocation and activation.…”

Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells

“…These receptors form an adaptive homeostatic network that bind lipophilic molecules, such as steroidal-based hormones, dietary factors, fatty acids and xenobiotics, with differing affinities to exert regulatory control over a wide range of gene targets (1)(2)(3). This network is integrated at multiple levels including ligand promiscuity, as demonstrated by the vitamin D receptor (VDR) and other receptors (4,5), and mutlimerisation.…”