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BXL‐628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA/Rho kinase signaling in rat and human bladder
Author(s) -
Morelli Annamaria,
Vignozzi Linda,
Filippi Sandra,
Vannelli Gabriella Barbara,
Ambrosini Stefano,
Mancina Rosa,
Crescioli Clara,
Donati Silvia,
Fibbi Benedetta,
Colli Enrico,
Adorini Luciano,
Maggi Mario
Publication year - 2006
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20463
Subject(s) - rhoa , rho associated protein kinase , endocrinology , medicine , cancer research , signal transduction , kinase , microbiology and biotechnology , chemistry , biology
BACKGROUND BXL‐628 is a calcitriol analog shown to decrease prostate growth in preclinical and clinical studies. BPH symptoms are generated not only by prostate overgrowth but also by bladder overactivity, resulting from an increased RhoA/Rho‐kinase signaling. Because bladder smooth muscle cells express VDR, we studied effects of BXL‐628 on this pathway. METHODS RhoA and Rho‐kinase gene expression and functional activity were studied in rat and human bladder smooth muscle by real‐time RT‐PCR, immuno‐kinase assays, western blot analysis, confocal microscopy, in vitro contractility, and cell migration. RESULTS In bladder smooth muscle, carbachol responsiveness was delayed and Rho‐kinase activity reduced by BXL‐628 treatment because of impaired RhoA membrane translocation and activation. Accordingly, RhoA‐mediated biological functions, such as cell migration and cytoskeleton remodeling were also inhibited by BXL‐628. CONCLUSIONS BXL‐628 inhibits RhoA/Rho‐kinase signaling, a calcium sensitizing pathway, suggesting its possible clinical use in the treatment of altered bladder contractility often associated with BPH‐induced lower urinary tract symptoms. Prostate 67:234–247, 2007. © 2006 Wiley‐Liss, Inc.