NSC 23766 trihydrochloride is a selective Rac1 GTPase inhibitor that suppresses Rac1 activation by specifically blocking the guanine nucleotide exchange factors Trio and Tiam1, with an IC₅₀ of approximately 50μM for Rac1[1-2]. NSC 23766 trihydrochloride effectively regulates various cellular functions including cytoskeletal reorganization, cell cycle progression, cell growth, adhesion, migration, and gene transcription, and is widely used in research related to cancer, inflammatory diseases, and neurobiology[3-4].
In vitro, pretreatment of rat pulmonary microvascular endothelial cells (PMVECs) with NSC 23766 trihydrochloride (50μM) for 48 hours, followed by treatment with common bile duct ligation (CBDL) rat serum for 12 or 24 hours, NSC 23766 trihydrochloride enhanced stress fiber formation and promoted PMVEC proliferation by inhibiting Rac1 activity[5]. Pretreatment of U251 human glioma cells with NSC 23766 trihydrochloride (50μM) for 0.5-4 hours, followed by cobalt-60 irradiation (0.5Gy/min, 10 minutes) and continued culture for 48 hours, NSC 23766 trihydrochloride significantly suppressed cell proliferation, migration, and invasion capabilities, downregulated cofilin-1 (CFL-1) protein expression, and thereby enhanced the radiosensitivity of U251 cells[6].
In vivo, continuous administration of NSC 23766 trihydrochloride (10mg/kg/day) via osmotic minipump for 7 weeks in an atherosclerosis mouse model, NSC 23766 trihydrochloride significantly reduced aortic Rac1 GTPase activity and NADPH oxidase activity, decreased vascular oxidative stress, improved endothelium-dependent vasodilation, and attenuated atherosclerotic plaque formation and macrophage infiltration[7]. In a C57BL/6 mouse model of cerebral stroke, intraperitoneal injection of NSC 23766 trihydrochloride (4.0mg/kg/day) for 7 days starting from day 7 post-stroke, NSC 23766 trihydrochloride significantly worsened motor function recovery, reduced axonal density in the peri-infarct zone, and decreased the activation of pro-regenerative molecules including p-LIMK1, p-MEK1/2, and p-ERK1/2[8].
References:
[1] Bailly C, Degand C, Laine W, et al. Implication of Rac1 GTPase in molecular and cellular mitochondrial functions. Life Sci. 2024 Apr 1;342:122510.
[2] Murphy NP, Mott HR, Owen D. Progress in the therapeutic inhibition of Cdc42 signalling. Biochem Soc Trans. 2021 Jun 30;49(3):1443-1456.
[3] Adam O, Laufs U. Rac1-mediated effects of HMG-CoA reductase inhibitors (statins) in cardiovascular disease. Antioxid Redox Signal. 2014 Mar 10;20(8):1238-50.
[4] Sooman L, Ekman S, Andersson C, et al. Synergistic interactions between camptothecin and EGFR or RAC1 inhibitors and between imatinib and Notch signaling or RAC1 inhibitors in glioblastoma cell lines. Cancer Chemother Pharmacol. 2013 Aug;72(2):329-40.
[5] Zeng J, Chen L, Chen B, et al. MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome. Cell Physiol Biochem. 2015;37(4):1289-300.
[6] Zhou T, Wang CH, Yan H, et al. Inhibition of the Rac1-WAVE2-Arp2/3 signaling pathway promotes radiosensitivity via downregulation of cofilin-1 in U251 human glioma cells. Mol Med Rep. 2016 May;13(5):4414-20.
[7] Zimmer S, Goody PR, Oelze M, et al. Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice. Front Cardiovasc Med. 2021 Aug 6;8:680775.
[8] Liu L, Yuan H, Yi Y, et al. Ras-Related C3 Botulinum Toxin Substrate 1 Promotes Axonal Regeneration after Stroke in Mice. Transl Stroke Res. 2018 Oct;9(5):506-514.
NSC 23766 trihydrochloride是一种选择性Rac1 GTPase抑制剂，通过特异性阻断Rac1的鸟嘌呤核苷酸交换因子Trio和Tiam1来抑制Rac1的激活，对Rac1的IC₅₀约为50μM[1-2]。NSC 23766 trihydrochloride 可有效调控细胞骨架重组、细胞周期进程、细胞生长、粘附、迁移和基因转录等多种细胞功能，被广泛应用于癌症、炎症性疾病以及神经生物学等相关领域的研究[3-4]。
在体外，NSC 23766 trihydrochloride（50μM）预处理大鼠肺微血管内皮细胞（PMVECs）48小时，随后用胆总管结扎（CBDL）大鼠血清处理12小时或24小时，NSC 23766 trihydrochloride通过抑制Rac1活性，增强了应力纤维的形成，并促进了PMVECs的增殖[5]。NSC 23766 trihydrochloride（50μM）预处理U251人胶质瘤细胞0.5-4小时，随后进行钴-60照射（0.5Gy/min，10分钟）并继续培养48小时，NSC 23766 trihydrochloride显著抑制了细胞的增殖、迁移和侵袭能力，并下调了cofilin-1（CFL-1）的蛋白表达，从而增强了U251细胞的放射敏感性[6]。
在体内，通过渗透性迷你泵持续给予NSC 23766 trihydrochloride（10mg/kg/天）处理动脉粥样硬化小鼠模型7周，NSC 23766 trihydrochloride显著降低主动脉Rac1 GTPase活性和NADPH氧化酶活性，减少血管氧化应激，改善内皮依赖性血管舒张功能，并减轻动脉粥样硬化斑块形成和巨噬细胞浸润[7]。在构建C57BL/6小脑卒中模型7天后，通过腹腔注射NSC 23766 trihydrochloride（4.0mg/kg/天）处理7天， NSC 23766 trihydrochloride显著恶化运动功能恢复，降低梗死周边区轴突密度，并减少p-LIMK1、p-MEK1/2和p-ERK1/2等促再生分子活化[8]。