Superior Antiproliferative and Enhanced Synergistic Effects of a ROCK Inhibitor in Multiple Models for Keloid Disease.

Keloid disease is a common fibroproliferative skin disorder characterized by excessive scar tissue formation and frequent recurrence. Limited therapies and study models hinder progress in addressing this unmet clinical need. AMA0825, a ROCK (Rho-associated protein kinase) inhibitor, has shown promising antifibrotic and antiproliferative effects in other fibrotic conditions. This study investigated the therapeutic potential of AMA0825 using in vitro, ex vivo, and a 3-dimensional spheroid model of keloid disease, which partially reflects features of the keloid microenvironment. AMA0825 demonstrated potent antiproliferative activity against keloid fibroblasts, with a half-maximal growth inhibitory concentration of 28.19 ± 1.6 nM, significantly outperforming dexamethasone (half-maximal growth inhibitory concentration = 35.35 ± 2.6 μM) and triamcinolone (half-maximal growth inhibitory concentration = 37.84 ± 3 μM). This effect was confirmed by decreased Ki-67 expression and cell cycle arrest at the G1 phase. In the 3-dimensional spheroid model, AMA0825 effectively inhibited cell proliferation at nanomolar concentrations, exceeding the efficacy of dexamethasone. Although AMA0825 did not demonstrate significant antifibrotic activity at lower concentrations, it exhibited antifibrotic effects at higher concentrations. In addition, synergistic effects were observed when combined with dexamethasone. This study highlights the potential of ROCK inhibitors, particularly AMA0825, as an antiproliferative agent for keloid disease and underscores the value of 3-dimensional spheroid models for evaluating alternative therapeutic strategies.