Z-VAD(OH)-FMK is an irreversible tripeptide inhibitor of all caspases[1]. Z-VAD(OH)-FMK is the unmethylated form of Z-VAD-FMK. Z-VAD(OH)-FMK inhibits the apoptosis process by covalently binding to the active site of caspase and preventing its activation, and can be used to study apoptosis-related immune responses [2].
In vitro, Z-VAD(OH)-FMK (50μM) treatment of Panc-1 and MIAPaca-2 cells for 1 hour effectively inhibited Rhein-induced cell death[3]. Z-VAD(OH)-FMK (0-100μM) treatment of T cells dose-dependently inhibited cell proliferation without blocking the processing of caspase-8 and caspase-3 proteins[4]. Z-VAD-FMK (40μM) treatment of HeLa cells for 30 minutes inhibited TSSLT-induced apoptosis[5].
In vivo, Z-VAD(OH)-FMK (3mg/kg) can inhibit caspase activation and prevent myocardial contractile dysfunction and cardiomyocyte apoptosis through intravenous injection in rats with endotoxin injury[6]. Z-VAD(OH)-FMK (1.5 mg/kg) was combined with carfilzomib to treat C26 adenocarcinoma cells inoculated mice, resulting in an increase in caspase-3 and BAX levels and a decrease in BCL-XL levels in the gastrocnemius muscle, regulating protein levels in the renin-angiotensin system[7].
References:
[1] Davies C W, Chaney J, Korbel G, et al. The co-crystal structure of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with a tripeptide fluoromethyl ketone (Z-VAE (OMe)-FMK)[J]. Bioorganic & medicinal chemistry letters, 2012, 22(12): 3900-3904.
[2] Rajah T, Chow S C. The inhibition of human T cell proliferation by the caspase inhibitor z-VAD-FMK is mediated through oxidative stress[J]. Toxicology and applied pharmacology, 2014, 278(2): 100-106.
[3] Liu Y, Shi C, He Z, et al. Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells[J]. International Journal of Biological Sciences, 2021, 17(2): 589.
[4] Lawrence C P, Chow S C. Suppression of human T cell proliferation by the caspase inhibitors, z-VAD-FMK and z-IETD-FMK is independent of their caspase inhibition properties[J]. Toxicology and applied pharmacology, 2012, 265(1): 103-112.
[5] Liu H R, Peng X D, He H B, et al. Antiproliferative activity of the total saponin of Solanum lyratum Thunb in Hela cells by inducing apoptosis[J]. Die Pharmazie-An International Journal of Pharmaceutical Sciences, 2008, 63(11): 836-842.
[6] NEVIÈRE R, FAUVEL H, CHOPIN C, et al. Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis[J]. American journal of respiratory and critical care medicine, 2001, 163(1): 218-225.
[7] Wang Q, Li C, Peng X, et al. Combined treatment of carfilzomib and z-VAD-fmk inhibits skeletal proteolysis and apoptosis and ameliorates cancer cachexia[J]. Medical oncology, 2015, 32: 1-10.
Z-VAD(OH)-FMK是所有半胱天冬酶的不可逆三肽抑制剂[1]。Z-VAD(OH)-FMK是Z-VAD-FMK的非甲基化形式。Z-VAD(OH)-FMK通过与半胱天冬酶的活性位点共价结合，阻止其活化，从而抑制细胞凋亡过程，可用于研究细胞凋亡相关的免疫反应[2]。
在体外，Z-VAD(OH)-FMK（50μM）处理Panc-1和MIAPaca-2细胞1h，有效抑制了莱茵（Rhein ）诱导的细胞死亡[3]。Z-VAD(OH)-FMK（0-100μM）处理T细胞，可剂量依赖性地抑制细胞增殖，但不阻断caspase-8和caspase-3蛋白的加工[4]。Z-VAD-FMK（40μM）处理HeLa细胞30min，抑制了TSSLT诱导的细胞凋亡[5]。
在体内，Z-VAD(OH)-FMK（3mg/kg）通过静脉注射治疗内毒素损伤大鼠，可以抑制半胱天冬酶激活，预防心肌收缩功能障碍和心肌细胞凋亡[6]。Z-VAD(OH)-FMK（1.5mg/kg）通过和卡非佐米联合治疗C26腺癌细胞接种小鼠，导致腓肠肌中caspase-3和BAX水平升高，BCL-XL水平降低，调节了肾素-血管紧张素系统中的蛋白质水平[7]。