一种ROCK抑制剂在多种瘢痕疙瘩疾病模型中具有卓越的抗增殖和增强的协同作用

Zeinab Ghasemishahrestani , Traci A. Wilgus , Nonhlanhla P. Khumalo , Ardeshir Bayat
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引用次数: 0

摘要

瘢痕疙瘩病是一种常见的纤维增生性皮肤疾病,其特征是瘢痕组织形成过多且经常复发。有限的治疗方法和研究模式阻碍了解决这一未满足的临床需求的进展。AMA0825是一种ROCK (rho相关蛋白激酶)抑制剂,在其他纤维化疾病中显示出有希望的抗纤维化和抗增殖作用。本研究通过体外、离体和瘢痕疙瘩病的三维球体模型来研究AMA0825的治疗潜力,该模型部分反映了瘢痕疙瘩微环境的特点。AMA0825对瘢痕疙瘩成纤维细胞表现出较强的抗增殖活性,半最大生长抑制浓度为28.19±1.6 nM,显著优于地塞米松(半最大生长抑制浓度为35.35±2.6 μM)和曲安奈德酮(半最大生长抑制浓度为37.84±3 μM)。Ki-67表达减少和细胞周期阻滞在G1期证实了这种作用。在三维球体模型中,AMA0825在纳摩尔浓度下有效抑制细胞增殖,超过地塞米松的效果。虽然AMA0825在低浓度下没有表现出明显的抗纤维化活性,但在高浓度下表现出抗纤维化作用。此外,与地塞米松合用可观察到协同效应。本研究强调了ROCK抑制剂,特别是AMA0825,作为瘢痕疙瘩疾病的抗增殖药物的潜力,并强调了三维球体模型在评估替代治疗策略方面的价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.
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