Fasudil (HA-1077; AT877) is a non-specific RhoA/ROCK inhibitor with a Ki of 0.33μM and an IC50 of 0.158μM for ROCK1, and IC50 of 4.58μM, 12.30μM, and 1.650μM for ROCK2, PKA, PKC, and PKG, respectively[1]. The monomeric G protein RhoA and its activated target Rho kinase (ROCK) constitute the RhoA/ROCK signaling pathway, which has the function of inducing cytoskeletal reorganization, cell migration, and stress fiber formation, and also affects endothelial permeability, tissue compatibility, cell proliferation, and apoptosis[2, 3]. Fasudil is also an effective Ca2+ channel antagonist and vasodilator[4].
In vitro, Fasudil (0-30μM) treatment of human bladder cancer cell lines (5637 and UM-UC-3 cells) for 72h inhibited cell proliferation and migration in a dose-dependent manner, induced cell apoptosis, and significantly reduced the expression of ROCK-I and ROCK-II[5]. Fasudil (0.04, 0.2, 1μg/mL) pre-treated the co-culture system established by neutrophils and human pulmonary microvascular endothelial cells (HPMECs) for 30min, reduced neutrophil transendothelial cell migration, and inhibited neutrophil endothelial chemotaxis[6]. Fasudil (100μM) treatment of rat hepatic stellate cells and human hepatic stellate cell-derived TWNT-4 cells inhibited cell extension, stress fiber formation, and α-SMA expression, stimulated the production and transcription of matrix metalloproteinase-1 (MMP-1), and enhanced collagenase activity[7].
In vivo, Fasudil (10mg/kg) was intravenously administered to mice after myocardial ischemia/reperfusion injury, inhibiting c-Jun N-terminal kinase (JNK)-mediated apoptosis-inducing factor (AIF) translocation and reducing cardiomyocyte apoptosis during ischemia/reperfusion[8].
References:
[1] Chen M, Liu A, Ouyang Y, et al. Fasudil and its analogs: a new powerful weapon in the long war against central nervous system disorders?[J]. Expert opinion on investigational drugs, 2013, 22(4): 537-550.
[2] Crosas-Molist E, Samain R, Kohlhammer L, et al. Rho GTPase signaling in cancer progression and dissemination[J]. Physiological Reviews, 2022, 102(1): 455-510.
[3] Radeva M Y, Waschke J. Mind the gap: mechanisms regulating the endothelial barrier[J]. Acta physiologica, 2018, 222(1): e12860.
[4] Chen Y, Yuan T, Zhang H, et al. Fasudil evokes vasodilatation of rat mesenteric vascular bed via Ca2+ channels and Rho/ROCK pathway[J]. European journal of pharmacology, 2016, 788: 226-233.
[5] Abe H, Kamai T, Hayashi K, et al. The Rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells[J]. BMC cancer, 2014, 14: 1-12.
[6] Wang J, Xu J, Zhao X, et al. Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2[J]. Experimental cell research, 2018, 365(1): 97-105.
[7] Fukushima M, Nakamuta M, Kohjima M, et al. Fasudil hydrochloride hydrate, a Rho‐kinase (ROCK) inhibitor, suppresses collagen production and enhances collagenase activity in hepatic stellate cells[J]. Liver international, 2005, 25(4): 829-838.
[8] Zhang J, Li X X, Bian H J, et al. Inhibition of the activity of Rho-kinase reduces cardiomyocyte apoptosis in heart ischemia/reperfusion via suppressing JNK-mediated AIF translocation[J]. Clinica Chimica Acta, 2009, 401(1-2): 76-80.
Fasudil（法舒地尔；HA-1077；AT877）是一种非特异性RhoA/ROCK抑制剂，对ROCK1的Ki为0.33μM，IC50为0.158μM，对ROCK2和PKA、PKC、PKG的IC50分别为4.58μM、12.30μM、1.650μM[1]。单体G蛋白RhoA及其激活靶点Rho激酶（ROCK）组成了RhoA/ROCK信号通路，该通路具有诱导细胞骨架重组、细胞迁移和应力纤维形成功能，还影响内皮通透性、组织相容性、细胞增殖、细胞凋亡等[2, 3]。Fasudil也是一种有效的Ca2+通道拮抗剂和血管扩张剂[4]。
在体外，Fasudil（0-30μM）处理人膀胱癌细胞系（5637和UM-UC-3细胞）72h，均以剂量依赖性方式抑制了细胞增殖和迁移，诱导了细胞凋亡，显著降低了ROCK-I和ROCK-II的表达[5]。Fasudil（0.04、0.2、1μg/mL）预处理中性粒细胞和人肺微血管内皮细胞（HPMECs）建立的共培养系统30min，减少了中性粒细胞跨内皮细胞迁移，抑制了中性粒细胞内皮趋化性[6]。Fasudil（100μM）处理大鼠肝星状细胞和人肝星状细胞来源的TWNT-4细胞，抑制了细胞伸展、应力纤维的形成和α-SMA的表达，刺激基质金属蛋白酶-1（MMP-1）的产生和转录，并增强胶原酶活性[7]。
在体内，Fasudil（10mg/kg）通过静脉注射治疗心脏缺血/再灌注损伤后的小鼠，抑制了c-Jun氨基末端激酶（JNK）介导的凋亡诱导因子（AIF）转位，减少了缺血再灌注时心肌细胞凋亡[8]。