Ezatiostat is a tripeptide analog of glutathione and a selective, orally active inhibitor of glutathione S-transferase P1-1 (GSTP1)[1-2]. By inhibiting GSTP1, Ezatiostat activates JNK, stimulates cell proliferation, and is applicable for research related to myelodysplastic syndromes (MDS)[3-4].
In vitro, Ezatiostat (0-20μM) was used to treat hepatocellular carcinoma cell lines such as Huh7, HepG2, and Hep3B for 72 hours. Ezatiostat directly targeted and inhibited GSTP1 enzyme activity, promoting the accumulation of reactive oxygen species (ROS) and inducing cellular senescence[5]. Ezatiostat (12.5μM) was also combined with the ALK inhibitor crizotinib to treat ALK-translocated lung adenocarcinoma (LUAD) patient-derived organoids (LUAD-OG1) for 14 days. Ezatiostat significantly inhibited tumor growth and enhanced the sensitivity of the organoids to crizotinib[6].
In vivo, Ezatiostat (50mg/kg; i.p.; administered every other day) was administered to an ovariectomized (OVX) mouse model for 1 month. Ezatiostat exacerbated OVX-induced osteoporosis[7]. Ezatiostat (0-30mg/kg; i.p.) was also used to pretreat C57BL/6J mice, which were exposed to alcohol 30 minutes later. Ezatiostat dose-dependently reduced the positive reinforcing effects of alcohol and inhibited nonspecific locomotor activity[8].
References:
[1] Shu G, Chen K, Li J, et al. Galangin alleviated Doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through GSTP1/JNK pathway. Phytomedicine. 2024 Nov;134:155989.
[2] Galili N, Tamayo P, Botvinnik OB, et al. Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome. J Hematol Oncol. 2012 May 6;5:20.
[3] Mahadevan D, Sutton GR. Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes. Expert Opin Investig Drugs. 2015 May;24(5):725-33.
[4] Raza A, Galili N, Smith SE, et al. A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome. Cancer. 2012 Apr 15;118(8):2138-47.
[5] Zhang Y, Xiao B, Yuan S, et al. Tryptanthrin targets GSTP1 to induce senescence and increases the susceptibility to apoptosis by senolytics in liver cancer cells. Redox Biol. 2024 Oct;76:103323.
[6] Wang SQ, Chen JJ, Jiang Y, et al. Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors. Adv Sci (Weinh). 2023 Mar;10(7):e2205262.
[7] Ji X, Hong J, Yang W, et al. GSTP1-mediated S-glutathionylation of Pik3r1 is a redox hub that inhibits osteoclastogenesis through regulating autophagic flux. Redox Biol. 2023 May;61:102635.
[8] Faccidomo S, Swaim KS, Saunders BL, et al, Eastman VR, Hodge CW. Mining the nucleus accumbens proteome for novel targets of alcohol self-administration in male C57BL/6J mice. Psychopharmacology (Berl). 2018 Jun;235(6):1681-1696.
Ezatiostat是一种谷胱甘肽的三肽类似物、选择性的口服活性的谷胱甘肽S-转移酶P1-1（GSTP1）抑制剂[1-2]。Ezatiostat通过抑制GSTP1导致JNK激活，刺激细胞增殖，可用于骨髓增生异常综合症（MDS）的相关研究[3-4]。
在体外，Ezatiostat（0-20μM）处理Huh7、HepG2和Hep3B等肝癌细胞72小时。Ezatiostat通过直接靶向抑制GSTP1酶活性，促进活性氧（ROS）的累积和细胞衰老[5]。Ezatiostat（12.5μM）与ALK抑制剂克唑替尼（crizotinib）联合处理ALK易位肺腺癌（LUAD）患者来源的类器官（LUAD-OG1）14天。Ezatiostat显著抑制了肿瘤生长，并增强了类器官对克唑替尼的敏感性[6]。
在体内，Ezatiostat（50mg/kg；i.p.；隔日一次）处理卵巢摘除（OVX）小鼠模型1个月。Ezatiostat加剧了OVX诱导的骨质疏松[7]。Ezatiostat（0-30mg/kg；i.p.）预处理C57BL/6J小鼠，30分钟后小鼠接受酒精刺激。Ezatiostat剂量依赖性地减少了酒精的正性强化效应。Ezatiostat可抑制非特异性运动[8]。