Apoptosis is mediated by specific initiating and effector cysteine proteases (caspases) that are unique in cleaving substrates specifically following aspartate residues. The activation of specific caspases has defined three major pathways that can carry out the apoptotic process[6]. Q-VD-OPh is an irreversible pan-caspase inhibitor with potent antiapoptotic properties, and it inhibits caspase 7 with IC50 of 48 nM and 25 - 400 nM for other caspases including caspase 1, 3, 8, 9, 10, and 12[7]. The broad spectrum caspase inhibitor, Boc-D-fmk, completely prevents apoptosis in WEHI 231 cells at 50 µM, but is ineffective at lower doses. In striking contrast, the caspase inhibitor Q-VD-OPh dramatically prevents DNA fragmentation at concentrations as low as 5 µM[6]. Analysis of 5 µM Q-VD-OPh in the presence of actinomycin D in WEHI 231 cells for at least 48 h results in no change in the cell number and complete cellular viability as determined by cell number and trypan blue exclusion[6]. Similar to WEHI 231 cells, the presence of 5 µM Q-VD-OPh completely prevents the actinomycin D-induced DNA fragmentation and apoptosis from occurring in Jurkat T cells[6]. TGF beta induced apoptosis in HRP-1 cells within 24 h, as determined by DNA laddering, and this is completely inhibited by 5 µM Q-VD-OPh, consistent with other cell lines[6]. C57BL/6 mice with ischemic ARF treated with Q-VD-OPh has a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice[8]. Two-day-old Swiss-Webster mice are infected with 104 PFU of myocarditic virus, followed by the administration of Q-VD-Oph, Z-VAD(OMe)-FMK, or their diluent controls on days 3 to 6 postinfection. Mice receiving caspase inhibitors shows statistically significant reductions in myocardial injury scores compared to controls, as measured by two independent myocardial injury scoring systems[9].
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