Z-VAD(OH)-FMK (Synonyms: Z-Val-Ala-Asp-(OH)-Fluoromethyl Ketone)

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.