Statins synergize with other drugs to prevent myofibroblast transformation in in vitro model of peyronie's disease

Abstract

Peyronie's disease is characterized by formation of a plaque in the tunica albuginea (TA), with myofibroblasts being the main effector cells. We have previously shown a synergy between phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) in inhibiting myofibroblast formation in models of PD. Further research revealed statins to be anti-fibrotic as well. Whilst the anti-fibrotic effect of statins themselves has already been described, we aimed to combine statins with our previously identified drugs. Tunica albuginea (TA) of PD patients was used to isolate primary fibroblasts. TA-derived fibroblasts were exposed to Transforming Growth Factor-ß1 (TGF-β1) and a range of concentrations of statins, PDE5i, SERM, and their combinations for 72h before quantifying α-smooth muscle actin (α-SMA) using In-Cell ELISA (ICE). Statins (simvastatin, lovastatin) showed a concentration dependent anti-fibrotic effect to prevent TGF-ß1-induced myofibroblast transformation, with IC50 values of 0.77 µM and 0.8 µM for simvastatin and lovastatin, respectively. Addition of 0.3 µM of simvastatin to a full concentration response curve of vardenafil revealed drug synergy, as 0.3 µM of simvastatin showed 12% inhibition, 0.3 µM of vardenafil 1.5% inhibition, but their combination exerted 33% inhibition. Similarly, 0.18 µM of tamoxifen showed 2% inhibition, whilst a combination with 0.3 µM simvastatin resulted in 24% inhibition. Interestingly, combining simvastatin, vardenafil, and tamoxifen was not more effective than vardenafil and tamoxifen, or vardenafil and simvastatin only. Statins, PDE5i, and SERMs are anti-fibrotic, and both double combinations (statin-PDE5i, statin-SERM) showed synergy in vitro. A triple combination did not exceed the double combinations. However, care must be taken with attempts to translate these results to bedside, as there have been reports of strong adverse effects in patients, such as myopathy due to metabolic toxicity, when treated with a statin-PDE5i combination. Authors hold patent for PDE5i-SERM use in fibrosis