Ilg Dr. Marcus M, Lapthorn Dr. Alice R, Ralph Prof. David J, Cellek Prof. Selim

(109) CONFIRMING ANTI-FIBROTIC EFFECT OF TERFENADINE, EBASTINE, AND SOLIFENACIN IN IN VITRO MODELS OF PEYRONIE’S DISEASE

  • Urology
  • Reproductive Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Psychiatry and Mental health
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Abstract Objectives Peyronie’s disease (PD) is characterised by formation of a fibrotic plaque in the tunica albuginea which is caused by excessive myofibroblast presence and activity. A previous phenotypic screening campaign that tested 1,954 FDA-approved drugs for their ability to inhibit myofibroblast transformation in PD-derived fibroblasts revealed 26 hits. Of these, we investigated the following hits further; terfenadine (H1-receptor antagonist), ebastine (H3-receptor antagonist) and solifenacin (muscarinic receptor antagonist). Methods Tunica albuginea of PD patients was used to isolate primary fibroblasts. The cells were treated with the drugs and co-incubated with transforming growth factor beta 1 (TGF-β1). Full concentration response curves ranging from 0.03 μM to 100 μM were constructed and myofibroblast transformation was quantified by measuring α-smooth muscle actin (α-SMA) using the In-Cell ELIA (ICE) method. A modified ICE was used to quantify total extracellular matrix (ECM) production. ICE results were further supported by Western blots and immunocytochemistry (ICC). Results Terfenadine (IC50 of 1.7 μM), ebastine (IC50 of 4.3 μM), and solifenacin (IC50 of 3.5 μM) showed a concentration-dependent inhibition of α-SMA in ICE which was confirmed by Western blot. ICC revealed that stress fibre formation was inhibited by all three drugs. The modified ICE confirmed concentration-dependent inhibition of ECM formation. Western blot analysis showed that terfenadine and ebastine but not solifenacin reduced fibronectin expression. Conclusions This is the first study to demonstrate that modulating H1-receptor, H3-receptor or muscarinic receptor signalling can affect myofibroblast transformation in PD-derived cells. These drugs have potential for repurposing for treatment of PD but need to be confirmed by in vivo studies. Conflicts of Interest None

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