P06 A Novel Drug Combination Produces a Synergistic Effect when Inhibiting Myofibroblast Transformation in an in Vitro Model of Hypertrophic Scarring

Abstract Introduction and aims Hypertrophic scars affect 91% of patients with burns and yet, there is currently no effective treatment for their prevention. Myofibroblasts are key cells in the pathogenesis of hypertrophic scars, with the inhibition of myofibroblast transformation having been suggested as an effective therapeutic strategy. We have previously screened 1954 drugs approved by the Food and Drug Administration to identify any that could inhibit myofibroblast transformation. Using this data, the aim of this study was to investigate the individual and combined antimyofibroblast effect of two drug classes. Methods Primary human fibroblasts were isolated from the scars of patients with burns, with myofibroblast transformation induced using transforming growth factor (TGF)-β1. Concentration-response curves for drug-class A and drug-class B were constructed at a range of concentrations (0.03–300 µmol L–1), with the In-Cell enzyme-linked immunosorbent assay method used to measure α-smooth muscle actin (α-SMA) expression. Combination experiments were carried out through construction of a concentration-response curve for drug-class A (0.03–100 µmol L–1) in the presence of 3 µmol L–1 of drug-class B. Results Both drug classes showed a concentration-dependent antimyofibroblast effect with an IC50 range of 12.2–120.1 µmol L–1 for drug-class A and 1.4–16.7 µmol L–1 for drug-class B. When given in combination the two classes of drugs produced a synergistic effect at all concentrations up to 10 µmol L–1. For example, an 18% reduction α-SMA expression was expected with 1 µmol L–1 of drug-class A and 3 µmol L–1 of drug-class B; however, a 24% reduction in α-SMA expression was observed instead. Conclusions This is the first study to identify this synergistic effect between these two drug classes, and therefore this novel drug combination could be developed for the prevention of hypertrophic scar formation.