Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models

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-b1induced 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.

Simvastatin and the Rho‐kinase inhibitor Y‐27632 prevent myofibroblast transformation in Peyronie's disease‐derived fibroblasts via inhibition of YAP/TAZ nuclear translocation

“…In PD, the origin of MFBs is ill‐investigated; nonetheless, it seems that TGF‐β1 is the common denominator. Thus, inhibition of TGF‐β1 signalling would probably impair MFB formation and subsequent fibrosis, regardless of the MFB origin, especially because TGF‐β1 has been previously described as a main driver of MFB transformation in PD , to the extent that the most widely used animal model of the disease is based on injection of the cytokine .…”

The Natural History of Peyronie's Disease

“…In the last few years, we acknowledged a growing interest in basic and translational research on PD pathogenesis, including the developing of the first in vitro cell culture models [10,11]. Even though, little progresses have been made towards further elucidating the real etiology of the disease.…”

Medical, non‐invasive, and minimally invasive treatment for Peyronie’s disease: A systematic review

“…A recent study showed that the combination of sildenafil and CCH is better in improving PD curvature associated with ED than CCH alone 40 . Another study on a rat model of PD had shown that vardenafil and tamoxifen may reduce myofibroblast alteration, collagen fiber contraction, and production of extracellular matrix in a synergistic manner 41 . Human studies that investigated the importance of chronic use of PDE5Is to treat penile deformity related to PD are rare; however, based on their wide availability and safety, the utilization of PDE5I in combination therapy for PD seems reasonable 42 …”