Epalrestat is an orally active inhibitor of aldose reductases AKR1B1 and AKR1B10, with IC50 values of 0.1µM and 0.33µM, respectively[1]. Epalrestat could protect against diabetic peripheral neuropathy by relieving oxidative stress and suppressing the polyol pathway[2]. Epalrestat has been widely used as an anti-cancer agent to inhibit the proliferation of various cancer cells[3].
In vitro, Epalrestat treatment for 24 hours significantly inhibited the accumulation of galactitol in IMS32 cells exposed to galactoseemia conditions with an IC50 value of 20nM, and reduced ROS production without affecting mitochondrial function[4]. Treatment with 100μM Epalrestat for 48 hours significantly inhibited the proliferation, migration and invasion of HeLa cells[5]. Treatment of bovine aortic endothelial cells (BAECs) with 100μM Epalrestat for 24 hours increased the level of Nrf2 in the cell nucleus and stimulated the expression of thioredoxin and heme oxygenase-1[6].
In vivo, Epalrestat treatment via daily oral administration of 35mg/kg for 10 weeks can improve the metabolic disorders and renal damage in a diabetic nephropathy rat model[7]. Oral administration of 50mg/kg/day of Epalrestat for 10 consecutive days significantly inhibited tumor growth in a xenograft mouse model of MDA-MB-231 cells[8].
References:
[1] Bailly C. Moving toward a new horizon for the aldose reductase inhibitor epalrestat to treat drug-resistant cancer[J]. European Journal of Pharmacology, 2022, 931: 175191.
[2] Li Q, Wang Z, Zhou W, et al. Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway[J]. Neural regeneration research, 2016, 11(2): 345-351.
[3] Wang C, Yan R, Luo D, et al. Aldo-keto reductase family 1 member B10 promotes cell survival by regulating lipid synthesis and eliminating carbonyls[J]. Journal of Biological Chemistry, 2009, 284(39): 26742-26748.
[4] Yako H, Niimi N, Takaku S, et al. Epalrestat Alleviates Reactive Oxygen Species and Endoplasmic Reticulum Stress by Maintaining Glycosylation in IMS32 Schwann Cells Under Exposure to Galactosemic Conditions[J]. International Journal of Molecular Sciences, 2025, 26(4): 1529.
[5] Ji J, Xu M X, Qian T Y, et al. The AKR1B1 inhibitor epalrestat suppresses the progression of cervical cancer[J]. Molecular Biology Reports, 2020, 47(8): 6091-6103.
[6] Yama K, Sato K, Abe N, et al. Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells[J]. Redox Biology, 2014, 4: 87.
[7] Song T, Wang R, Zhou X, et al. Metabolomics and molecular dynamics unveil the therapeutic potential of epalrestat in diabetic nephropathy[J]. International Immunopharmacology, 2024, 140: 112812.
[8] Wu X, Li X, Fu Q, et al. AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program[J]. Journal of Experimental Medicine, 2017, 214(4): 1065-1079.
Epalrestat是一种口服有效的醛糖还原酶抑制剂，对AKR1B1和AKR1B10的IC50值分别为0.1µM和0.33µM[1]。Epalrestat通过缓解氧化应激及抑制多元醇通路，对糖尿病周围神经病变具有保护作用[2]。Epalrestat已作为抗癌剂广泛应用于多种癌细胞的增殖抑制研究[3]。
在体外，Epalrestat处理24小时能显著抑制半乳糖血症条件下IMS32细胞中半乳糖醇的积累，IC50值为20nM，同时降低ROS生成且不影响线粒体功能[4]。使用100µM的Epalrestat处理HeLa细胞48小时，可显著抑制细胞的增殖、迁移和侵袭能力[5]。用100µM的Epalrestat处理牛主动脉内皮细胞(BAECs)24小时，能提高细胞核内Nrf2水平，并刺激硫氧还蛋白和血红素加氧酶-1的表达[6]。
在体内，每日口服35mg/kg剂量的Epalrestat连续10周，可改善糖尿病肾病大鼠模型的代谢紊乱和肾脏损伤[7]。连续10日每日口服50mg/kg/day剂量的Epalrestat，能显著抑制MDA-MB-231细胞移植瘤小鼠的肿瘤生长[8]。