Dose-dependent effects of the caspase inhibitor Q-VD-OPh on different apoptosis-related processes
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
21751237
DOI
10.1002/jcb.23263
Knihovny.cz E-resources
- MeSH
- Apoptosis drug effects MeSH
- Cell Adhesion MeSH
- Quinolines pharmacology MeSH
- Amino Acid Chloromethyl Ketones pharmacology MeSH
- Electrophoresis, Polyacrylamide Gel MeSH
- Cysteine Proteinase Inhibitors pharmacology MeSH
- Caspase Inhibitors * MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Dose-Response Relationship, Drug MeSH
- Blotting, Western MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Quinolines MeSH
- Amino Acid Chloromethyl Ketones MeSH
- Cysteine Proteinase Inhibitors MeSH
- Caspase Inhibitors * MeSH
- quinoline-val-asp(OMe)-CH2-OPH MeSH Browser
The effects of the pan-caspase inhibitor Q-VD-OPh on caspase activity, DNA fragmentation, PARP cleavage, 7A6 exposition, and cellular adhesivity to fibronectin were analyzed in detail in three different apoptotic systems involving two cell lines (JURL-MK1 and HL60) and two apoptosis inducers (imatinib mesylate and suberoylanilide hydroxamic acid). Q-VD-OPh fully inhibited caspase-3 and -7 activity at 0.05 µM concentration as indicated both by the measurement of the rate of Ac-DEVD-AFC cleavage and anti-caspase immunoblots. Caspase-8 was also inhibited at low Q-VD-OPh concentrations. On the other hand, significantly higher Q-VD-OPh dose (10 µM) was required to fully prevent the cleavage of PARP-1. DNA fragmentation and disruption of the cell membrane functionality (Trypan blue exclusion test) were both prevented at 2 µM Q-VD-OPh while 10 µM inhibitor was needed to inhibit the drug-induced loss of cellular adhesivity to fibronectin which was observed in JURL-MK1 cells. The exposition of the mitochondrial antigen 7A6 occurred independently of Q-VD-OPh addition and may serve to the detection of cumulative incidence of the cells which have initiated the apoptosis. Our results show that Q-VD-OPh efficiency in the inhibition of caspase-3 activity and DNA fragmentation in the whole-cell environment is about two orders of magnitude higher than that of z-VAD-fmk. This difference is not due to a slow permeability of the latter through the cytoplasmic membrane.
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