Journal
EUROPEAN UROLOGY
Volume 75, Issue 2, Pages 329-340Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.eururo.2018.10.014
Keywords
Peyronie's disease; Fibroblast; Myofibroblast; Fibrosis; Fibroproliferative; Phosphodiesterase type; 5 inhibitor; Oestrogen receptor modulator; Tunica albuginea; Phenotypic screening
Categories
Funding
- European Society for Sexual Medicine
- NIHR Biomedical Research Centre, University College London Hospital
Ask authors/readers for more resources
Background: Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option. Objective: To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD. Design, setting, and participants: We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD. Results and limitations: The new assay was able to detect transforming growth factor-beta 1-induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy. Conclusions: This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models. Patient summary: This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase. (C) 2018 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available