Antifibrotic synergy between phosphodiesterase type 5 inhibitors and selective oestrogen receptor modulators in Peyronie’s disease models

Ilg, Marcus M. and Mateus, Marta and Stebbeds, William J. and Milenkovic, Uros and Christopher, Nim and Muneer, Asif and Albersen, Maarten and Ralph, David J. and Cellek, Selim (2019) Antifibrotic synergy between phosphodiesterase type 5 inhibitors and selective oestrogen receptor modulators in Peyronie’s disease models. European Urology, 75 (2). pp. 329-340. ISSN 1873-7560

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Official URL: https://doi.org/10.1016/j.eururo.2018.10.014

Abstract

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-β1–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.

Item Type: Journal Article
Keywords: Peyronie’s disease, fibroblast, myofibroblast, fibrosis, fibroproliferative, PDE5 inhibitor, oestrogen receptor modulator, tunica albuginea, phenotypic screening
Faculty: Faculty of Health, Education, Medicine & Social Care
Depositing User: Ian Walker
Date Deposited: 01 Oct 2018 07:59
Last Modified: 14 Nov 2019 16:08
URI: http://arro.anglia.ac.uk/id/eprint/703630

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