Z-IETD-FMK

Z-IETD-FMK (Z-IE(OMe)TD(OMe)-FMK) is a selective and cell-permeable inhibitor of caspase-8^[1]. Caspase-8 is a member of the cysteine ​​protease family and is involved in apoptosis and cytokine processing^[2]. Z-IETD-FMK is also a granzyme B inhibitor^[3].

In vitro, treatment of peripheral blood mononuclear cells (PBMCs) with Z-IETD-FMK (100μM) for 24h significantly inhibited mitogen-induced T cell proliferation and blocked the nuclear translocation of NF-κB RelA (p65) in activated T cells^[4].

In vivo, treatment of SHIP1^−/− mice with Z-IETD-FMK (5mg/kg) by intraperitoneal injection for 3 weeks significantly reduced the anatomical pathological features of the small intestine and lungs of the mice and significantly restored the number of viable CD3⁺ T cells, while mice treated with vehicle showed T cell deficiency^[5]. Intratracheal injection of Z-IETD-FMK (0.5μg) into lung cancer-bearing mice significantly reduced the number of proliferative cells, lung tumor formation, and lung tumor foci, reduced Ki-67-positive cells, and decreased the levels of IL-6, TNF-α, and IL-18 in bronchoalveolar fluid (BAL)^[6].

References:
[1] Xu J, Tan Z C, Shen Z Y, et al. Cordyceps cicadae polysaccharides inhibit human cervical cancer hela cells proliferation via apoptosis and cell cycle arrest[J]. Food and Chemical Toxicology, 2021, 148: 111971.
[2] Tummers B, Green D R. Caspase‐8: regulating life and death[J]. Immunological reviews, 2017, 277(1): 76-89.
[3] Toda H, Yabu T, Shiba H, et al. Evaluating antigen-specific cytotoxicity of CD8+ T cells in fish by granzyme B-like activity[J]. Veterinary immunology and immunopathology, 2011, 141(1-2): 168-172.
[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] Park M Y, Srivastava N, Sudan R, et al. Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice[J]. Mucosal immunology, 2014, 7(6): 1429-1439.
[6] Terlizzi M, Di Crescenzo V G, Perillo G, et al. Pharmacological inhibition of caspase‐8 limits lung tumour outgrowth[J]. British Journal of Pharmacology, 2015, 172(15): 3917-3928.

Z-IETD-FMK（Z-IE(OMe)TD(OMe)-FMK）是一种选择性和细胞可渗透的 caspase-8抑制剂^[1]。Caspase-8是半胱氨酸蛋白酶的成员，与细胞凋亡和细胞因子加工有关^[2]。Z-IETD-FMK也是一种颗粒酶B抑制剂^[3]。

在体外，Z-IETD-FMK（100μM）处理外周血单核细胞（PBMCs）24h，可显著抑制丝裂原诱导的T细胞增殖，阻断活化T细胞NF-κB RelA（p65）核转位^[4]。

在体内，Z-IETD-FMK（5mg/kg）通过腹腔注射治疗SHIP1^−/−小鼠3周，显著减少了小鼠的小肠和肺部解剖病理学特征，显著恢复了存活的CD3⁺ T细胞数量，而用载体治疗的小鼠则表现出T细胞缺乏^[5]。Z-IETD-FMK（0.5μg）通过气管内注射治疗肺癌荷瘤小鼠，显著减少了增生细胞、肺肿瘤形成和肺肿瘤灶数目，减少了Ki-67阳性细胞，降低了支气管肺泡液（BAL）中IL-6、TNF-α、IL-18的水平^[6]。