Marcus M Ilg1, Marta Mateus1, William J Stebbeds2, Uros Milenkovic3, Nim Christopher4, Asif Muneer5, Maarten Albersen3, David J Ralph6, Selim Cellek7. 1. Anglia Ruskin University, Chelmsford, UK. 2. Cranfield University, UK. 3. KU Leuven, Leuven, Belgium. 4. University College London Hospital, London, UK. 5. University College London Hospital, London, UK; NIHR Biomedical Research Centre, University College London Hospital, London, UK; University College London, London, UK. 6. University College London Hospital, London, UK; University College London, London, UK. 7. Anglia Ruskin University, Chelmsford, UK. Electronic address: selim.cellek@anglia.ac.uk.
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.
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.
Authors: Benjamin P Sharpe; Annette Hayden; Antigoni Manousopoulou; Andrew Cowie; Robert C Walker; Jack Harrington; Fereshteh Izadi; Stella P Breininger; Jane Gibson; Oliver Pickering; Eleanor Jaynes; Ewan Kyle; John H Saunders; Simon L Parsons; Alison A Ritchie; Philip A Clarke; Pamela Collier; Nigel P Mongan; David O Bates; Kiren Yacqub-Usman; Spiros D Garbis; Zoë Walters; Matthew Rose-Zerilli; Anna M Grabowska; Timothy J Underwood Journal: Cell Rep Med Date: 2022-06-21
Authors: Fabrizio Di Maida; Gianmartin Cito; Luca Lambertini; Francesca Valastro; Girolamo Morelli; Andrea Mari; Marco Carini; Andrea Minervini; Andrea Cocci Journal: World J Mens Health Date: 2020-07-08 Impact factor: 5.400