Avasimibe is a selective and oral acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor (IC50=12μmol/L)[1]. Avasimibe suppressed CYP2C9 (IC50=2.9μmol/L), CYP1A2 (IC50=13.9μmol/L), and CYP2C19 (IC50=26.5 μμmol/L)[2]. Avasimibe has been used in lipid-lowering research and anti-cancer research[3].
In vitro, Avasimibe demonstrated a dose-dependent suppression of U251 and U87 human glioblastoma cell proliferation with IC50 values of 20.29μmol/L and 28.27μmol/L, respectively after 48 hours of treatment[4]. When exposed to Avasimibe for 48 hours at 30μmol/L, U251 and U87 human glioblastoma cells showed decreased DNA synthesis together with suppressed cell clone formation[4]. The prostate cancer cells PC-3 and DU 145 showed decreased viability after receiving Avasimibe treatment at 20μmol/L concentration over 72 hours, which led to decreased sterol O-acyltransferase (SOAT) expression levels[5]. Avasimibe treatment at 20μmol/L for 48 hours reduced T24 cell proliferation and migration while increasing intracellular reactive oxygen species (ROS) production, accompanied by the upregulation of the expressions of ROS metabolism-related proteins SOD2 and catalase[6].
In vivo, Avasimibe treatment (25mg/kg/day; 28 days) via oral administration to miniature pigs fed a fat- and cholesterol-containing diet significantly decreased the secretion of hepatic apolipoprotein (apo) B containing lipoproteins into plasma[7]. In the asthma mouse model, intratracheal injection of Avasimibe at 20mg/kg significantly reduced the production of IL-4 and IL-5 in bronchoalveolar lavage fluid (BALF) and total IgE in serum, resulting in reduced mucus secretion in the airway epithelium of mice, decreased goblet cells and basal cells[8].
References:
[1] Llaverías G, Laguna J C, Alegret M. Pharmacology of the AC AT Inhibitor Avasimibe (CI‐1011)[J]. Cardiovascular drug reviews, 2003, 21(1): 33-50.
[2] Sahi J, Stern R H, Milad M A, et al. Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo[J]. Drug metabolism and disposition, 2004, 32(12): 1370-1376.
[3] Tardif J C, Grégoire J, L’Allier P L, et al. Effects of the acyl coenzyme A: cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions[J]. Circulation, 2004, 110(21): 3372-3377.
[4] Liu J, Fu W, Zheng X, et al. Avasimibe exerts anticancer effects on human glioblastoma cells via inducing cell apoptosis and cell cycle arrest[J]. Acta Pharmacologica Sinica, 2021, 42(1): 97-107.
[5] Xiong K, Wang G, Peng T, et al. The cholesterol esterification inhibitor avasimibe suppresses tumour proliferation and metastasis via the E2F-1 signalling pathway in prostate cancer[J]. Cancer Cell International, 2021, 21: 1-13.
[6] Peng T, Xiong K, He Z, et al. Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer[J]. Journal of Cancer, 2024, 15(2): 370.
[7] Burnett J R, Telford D E, Barrett P H R, et al. The ACAT inhibitor avasimibe increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs[J]. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 2005, 1738(1-3): 10-18.
[8] Zhou Z, Liang S, Zhou Z, et al. Avasimibe alleviates disruption of the airway epithelial barrier by suppressing the wnt/β-catenin signaling pathway[J]. Frontiers in Pharmacology, 2022, 13: 795934.
Avasimibe是一种选择性口服酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂（IC50=12μmol/L）[1]。Avasimibe对CYP2C9（IC50=2.9μmol/L）、CYP1A2（IC50=13.9μmol/L）和CYP2C19（IC50=26.5μmol/L）具有抑制作用[2]。Avasimibe已被应用于降脂研究和抗癌研究[3]。
在体外，Avasimibe处理48小时后能剂量依赖性抑制U251和U87人胶质母细胞瘤细胞的增殖，IC50值分别为20.29μmol/L和28.27μmol/L[4]。当以30μmol/L浓度的Avasimibe处理48小时后，U251和U87细胞不仅DNA合成减少，细胞克隆形成能力也受到抑制[4]。在前列腺癌细胞PC-3和DU 145中，20μmol/L浓度的Avasimibe处理72小时可降低细胞活力，同时下调固醇O-酰基转移酶（SOAT）表达水平[5]。20μmol/L浓度的Avasimibe处理T24细胞48小时能抑制细胞增殖和迁移，同时增加细胞内活性氧（ROS）生成，并上调ROS代谢相关蛋白SOD2和过氧化氢酶的表达[6]。
在体内，高脂高胆固醇饮食的小型猪在连续28天口服25mg/kg/day剂量的Avasimibe后，肝脏分泌含载脂蛋白B（apoB）的脂蛋白进入血浆的量显著减少[7]。在哮喘小鼠模型中，20mg/kg剂量的Avasimibe经气管内注射可显著降低支气管肺泡灌洗液（BALF）中IL-4、IL-5水平及血清总IgE含量，减少小鼠气道上皮黏液分泌，同时降低杯状细胞和基底细胞数量[8]。