Rhosin hydrochloride is a potent and specific small-molecule inhibitor of the RhoA subfamily of Rho GTPases. Rhosin hydrochloride selectively binds to RhoA and inhibits the interaction between RhoA and guanine nucleotide exchange factors (GEFs), with a dissociation constant (Kd) of approximately 0.4μM[1]. Rhosin hydrochloride can inhibit the proliferation and migration of cancer cells[2], suppress RhoA-mediated cytokinesis[3], and impede platelet activation by inhibiting reactive oxygen species (ROS) generation[4].
In vitro, pretreatment of BRCA1-mutated basal-like breast cancer cells SUM1315-LXSN and MDA-MB-231 with Rhosin hydrochloride (30μM) for 24 hours significantly inhibited cell migration and invasion, while reducing stress fiber formation[5]. In vascular smooth muscle cells from spontaneously hypertensive rats, co-administration of Rhosin hydrochloride (25μM) with Y16 for 24 hours, followed by angiotensin II (0.1μM) stimulation for 10 minutes, markedly suppressed the interaction between LARG and RhoA, decreased MYPT1 phosphorylation, and attenuated calcium sensitization pathway activity[6].
In vivo, intraperitoneal administration of Rhosin hydrochloride (40mg/kg) 15 minutes before chronic stress exposure for 10 consecutive days in C57BL/6J mice significantly inhibited hyperexcitability and loss of excitatory input in nucleus accumbens D1-MSNs, increased dendritic spine density, and promoted stress resilience[7]. Daily intraperitoneal injection of Rhosin hydrochloride (10–30mg/kg) for 14 days in 8‑week‑old C57BL/6J and Balb/c mice notably suppressed the formation of lung metastatic nodules from B16BL6 melanoma and 4T1 breast cancer cells, while reducing the expression of metastasis‑related proteins RHAMM and CXCR4[8].
References:
[1] Shang X, Marchioni F, Sipes N, et al. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem Biol. 2012 Jun 22;19(6):699-710.
[2] Kim JH, Park S, Lim SM, et al. Rational design of small molecule RHOA inhibitors for gastric cancer. Pharmacogenomics J. 2020 Aug;20(4):601-612.
[3] Duan X, Liu J, Zhu CC, Chen Z, et al. RhoA-mediated MLC2 regulates actin dynamics for cytokinesis in meiosis. Cell Cycle. 2016;15(3):471-7.
[4] Akbar H, Duan X, Saleem S, et al. RhoA and Rac1 GTPases Differentially Regulate Agonist-Receptor Mediated Reactive Oxygen Species Generation in Platelets. PLoS One. 2016 Sep 28;11(9):e0163227.
[5] Privat M, Cavard A, Zekri Y, et al. A high expression ratio of RhoA/RhoB is associated with the migratory and invasive properties of basal-like Breast Tumors. Int J Med Sci. 2020 Oct 1;17(17):2799-2808.
[6] Chiu WC, Chiang JY, Chiang FT. Small chemical compounds Y16 and Rhosin can inhibit calcium sensitization pathway in vascular smooth muscle cells of spontaneously hypertensive rats. J Formos Med Assoc. 2021 Oct;120(10):1863-1868.
[7] Francis TC, Gaynor A, Chandra R, et al. The Selective RhoA Inhibitor Rhosin Promotes Stress Resiliency Through Enhancing D1-Medium Spiny Neuron Plasticity and Reducing Hyperexcitability. Biol Psychiatry. 2019 Jun 15;85(12):1001-1010.
[8] Tsubaki M, Genno S, Takeda T, et al. Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells. Biomedicines. 2021 Jan 4;9(1):35.
Rhosin hydrochloride是一种有效的、特异性的RhoA亚家族Rho GTPases小分子抑制剂，能够特异性地结合RhoA并抑制RhoA与鸟嘌呤核苷酸交换因子（GEF）的相互作用，其解离常数（Kd）约为0.4μM[1]。Rhosin hydrochloride可抑制癌细胞的增殖和迁移能力[2]。Rhosin hydrochloride可抑制由RhoA介导的胞质分裂[3]。Rhosin hydrochloride通过抑制活性氧（ROS）的生成来阻碍血小板的活化[4]。
在体外，Rhosin hydrochloride（30μM）预处理BRCA1突变型基底样乳腺癌细胞SUM1315-LXSN及MDA-MB-231细胞24小时，显著抑制细胞的迁移和侵袭能力，同时降低应激纤维的形成 [5]。Rhosin hydrochloride（25μM）联合Y16预处理自发性高血压大鼠血管平滑肌细胞24小时，随后以血管紧张素II（0.1μM）刺激10分钟，Rhosin hydrochloride显著抑制LARG与RhoA的相互作用及MYPT1磷酸化水平，同时减弱钙离子敏化通路活性[6]。
在体内，Rhosin hydrochloride（40mg/kg）于慢性应激前15分钟腹腔注射处理C57BL/6J小鼠，连续10天，Rhosin hydrochloride显著抑制伏隔核D1-MSN神经元的超兴奋性及兴奋性输入减少，同时增强树突棘密度并促进应激恢复能力[7]。Rhosin hydrochloride（10-30mg/kg）每日腹腔注射处理8周龄C57BL/6J及Balb/c小鼠，连续14天，显著抑制黑色素瘤细胞B16BL6及乳腺癌细胞4T1的肺转移结节形成，同时降低转移相关蛋白RHAMM与CXCR4的表达[8]。