Boc-D-FMK

Boc-D-FMK is a cell-permeable broad-spectrum caspase inhibitor that fully inhibits the pro-apoptotic effect of tumor necrosis factor-α (TNFα) with the half maximal inhibition concentration IC50 value of 39 μM [1].

Boc-D-FMK has been found to reduce the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-kB), suppress the phosphorylation of subunit nuclear factor kappa light polypeptide gene enhancer in B cells inhibitor α (IkBα) and inhibits TNF-induced expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [2].

Moreover, Boc-D-FMK has also effectively attenuated the hepatocyte apoptosis in bile duct-ligated rats potentially improving the survival rates [3].

References:
[1] Cowburn AS, White JF, Deighton J, Walmsley SR, Chilvers ER. z-VAD-fmk augmentation of TNF alpha-stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species. Blood. 2005 Apr 1;105(7):2970-2. Epub 2004 Nov 30.
[2] Wu X, Guo R, Chen P, Wang Q, Cunningham PN. TNF induces caspase-dependent inflammation in renal endothelial cells through a Rho- and myosin light chain kinase-dependent mechanism. Am J Physiol Renal Physiol. 2009 Aug;297(2):F316-26. doi: 10.1152/ajprenal.00089.2009. Epub 2009 May 6.
[3] Sheen-Chen SM, Hung KS, Eng HL. Effect of Boc-D-Fmk on hepatocyte apoptosis after bile duct ligation in rat and survival rate after endotoxin challenge. J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1):1276-9. doi: 10.1111/j.1440-1746.2008.05368.x. Epub 2008 Mar 27.

Effect of Boc-D-Fmk on hepatocyte apoptosis after bile duct ligation in rat and survival rate after endotoxin challenge.[Pubmed:18373562]

J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1):1276-9.

BACKGROUND AND AIM: Retention and accumulation of toxic hydrophobic bile salts within hepatocytes may cause hepatocyte toxicity by inducing apoptosis. Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. Boc-D-FMK is a cell-permeable irreversible inhibitor of caspase and recent data suggest that it might block the processing of many caspases. The purpose of the present study was to evaluate the possible effect of Boc-D-FMK on hepatocyte apoptosis and on survival rate after bile duct ligation in the rat. METHODS: Male Sprague-Dawley rats, weighing 280-300 g were randomized to three groups of eight rats each. Group 1 (OBBOC-D) underwent common bile duct ligation and simultaneous treatment with Boc-D-FMK-fmk (dissolved in dimethylsulfoxide [DMSO]). Group 2 (OBZFA) underwent common bile duct ligation and simultaneous treatment with ZFA-fmk (dissolved in DMSO). Group 3 (SHAM) underwent sham operation and simultaneous treatment with the same amount of dimethylsulfoxide (DMSO, n = 4) or the same amount of normal saline (n = 4). After 3 days, liver tissue was harvested for histopathological analysis and measurements of apoptosis. Survival rates were measured in a separate experiment in which animals underwent the same protocol. The animals received endotoxin (15 mg/kg) in the afternoon of the third postoperative day. Animals were observed for 48 h and the survival rates were recorded. RESULTS: When compared with sham operation, common bile duct ligation with ZFA-fmk (placebo) significantly increased hepatocyte apoptosis (P < 0.001). When compared with the OBZFA group, Boc-D-FMK significantly diminished the increased hepatocyte apoptosis in the OBBOC-D group (P < 0.001). There is no difference in hepatocyte apoptosis (P = 0.05) between OBBOC-D and SHAM groups. After endotoxin challenge, the 48 h survival rates were 100%, 87.5% and 62.5% for the SHAM, OBBOC-D and OBZFA groups, respectively. CONCLUSIONS: Boc-D-FMK-fmk effectively attenuated the hepatocyte apoptosis in bile duct-ligated rats and may improve the survival rates after endotoxin challenge.