Z-VDVAD-FMK

Z-VDVAD-FMK is an irreversible, cell-permeable caspase-2-specific inhibitor^[1-2]. By specifically binding to the active site of caspase-2, Z-VDVAD-FMK effectively blocks caspase-2 signaling pathway, thereby inhibiting the activation of downstream caspases (such as caspase-3) and suppressing apoptosis^[3-4].

In vitro, BxPC-3 human pancreatic carcinoma cells were pretreated with Z-VDVAD-FMK (50μM) for 3 hours, followed by treatment with PS-341 (Bortezomib; 100nM) for 24 hours. Z-VDVAD-FMK significantly inhibited PS-341-induced mitochondrial depolarization and apoptosis, and blocked the changes in mitochondrial permeability downstream of caspase-2 activation^[5]. HL-60 acute myeloid leukemia cells were pretreated with Z-VDVAD-FMK (10μM) for 2 hours, followed by treatment with Gemtuzumab ozogamicin (GO; 1000ng/mL) for 48 hours. Z-VDVAD-FMK significantly inhibited GO-induced caspase-3 activation and reduced apoptotic signaling. Under GO treatment, Z-VDVAD-FMK also partially inhibited Bid cleavage^[6].

In vivo, Z-VDVAD-FMK (400–5000ng/mL; 5μL) was administered via intravitreal injection (on days 0, 4, 8, and 12) in an optic nerve crush (ONC) injury Sprague-Dawley rats model. Z-VDVAD-FMK significantly inhibited ONC-induced caspase-2 activation and reduced the level of apoptosis in retinal ganglion cells^[7].

References:
[1] Gamen S, Anel A, Pérez-Galán P, et al. Doxorubicin treatment activates a Z-VAD-sensitive caspase, which causes deltapsim loss, caspase-9 activity, and apoptosis in Jurkat cells. Exp Cell Res. 2000 Jul 10;258(1):223-35.
[2] Sapet C, Simoncini S, Loriod B, et al. I Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2. Blood. 2006 Sep 15;108(6):1868-76.
[3] Rabkin SW, Kong JY. Lovastatin-induced cardiac toxicity involves both oncotic and apoptotic cell death with the apoptotic component blunted by both caspase-2 and caspase-3 inhibitors. Toxicol Appl Pharmacol. 2003 Dec 15;193(3):346-55.
[4] Kim BM, Hong SH. Sequential caspase-2 and caspase-8 activation is essential for saikosaponin a-induced apoptosis of human colon carcinoma cell lines. Apoptosis. 2011 Feb;16(2):184-97.
[5] Yeung BH, Huang DC, Sinicrope FA. PS-341 (bortezomib) induces lysosomal cathepsin B release and a caspase-2-dependent mitochondrial permeabilization and apoptosis in human pancreatic cancer cells. J Biol Chem. 2006 Apr 28;281(17):11923-32.
[6] Hååg P, Olsson M, Forsberg J, et al. Caspase-2 is a mediator of apoptotic signaling in response to gemtuzumab ozogamicin in acute myeloid leukemia. Cell Death Discov. 2022 Jun 11;8(1):284.
[7] Vigneswara V, Berry M, Logan A, et al. Pharmacological inhibition of caspase-2 protects axotomised retinal ganglion cells from apoptosis in adult rats. PLoS One. 2012;7(12):e53473.

Z-VDVAD-FMK是一种不可逆的、具有细胞渗透性的caspase-2特异性抑制剂^[1-2]。Z-VDVAD-FMK通过特异性结合caspase-2的活性中心，有效阻断其激活下游caspase（如caspase-3）的信号通路，从而抑制细胞凋亡^[3-4]。

在体外，Z-VDVAD-FMK（50μM）预处理BxPC-3人胰腺癌细胞3小时，随后使用PS-341（Bortezomib；100nM）处理24小时，Z-VDVAD-FMK显著抑制PS-341诱导的线粒体去极化和凋亡，并阻断caspase-2激活下游的线粒体通透性改变^[5]。Z-VDVAD-FMK（10μM）预处理HL60急性髓系白血病细胞2小时，随后使用Gemtuzumab ozogamicin（GO；1000ng/mL）处理48小时，Z-VDVAD-FMK显著抑制GO诱导的caspase-3活化，并减少凋亡信号传导；在GO处理条件下，Z-VDVAD-FMK还部分抑制了Bid的切割^[6]。

在体内，Z-VDVAD-FMK（400-5000ng/ml；5μl）通过视玻璃体内注射（在第0,4,8,12天给药）处理视神经压迫（ONC）损伤Sprague-Dawley大鼠模型。Z-VDVAD-FMK显著抑制了ONC诱导的caspase-2活化，降低视网膜神经节细胞的凋亡水平^[7]。