Document Detail


The broad-spectrum caspase inhibitor Boc-Asp-CMK induces cell death in human leukaemia cells.
MedLine Citation:
PMID:  18434077     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Synthetic caspase inhibitors and particularly broad-spectrum caspase inhibitors can prevent cells from death or at least slow down cell death process and abrogate some apoptotic hallmarks [Kitanaka, C., Kuchino, Y., 1999. Caspase-independent programmed cell death with necrotic morphology. Cell Death and Differentiation 6, 508-515]. However, not all synthetic caspase inhibitors diminish cell death. We have found that the broad-spectrum caspase inhibitor Boc-Asp-CMK induced cell death at micromolar concentrations in human leukaemia cells. Interestingly, low concentrations of Boc-Asp-CMK induced cell death with apoptotic hallmarks. Increasing concentrations of Boc-Asp-CMK led to necrotic cell death. The switch between apoptosis and necrosis seemed to depend upon the degree of inhibition of executioner caspases, including caspase-3/7 with Boc-Asp-CMK. Interestingly, caspase-3 processing was not inhibited even for the highest concentration of Boc-Asp-CMK used. We assume, that toxic properties of Boc-Asp-CMK can be attributed to the chloromethylketone residuum in its molecule, as its analogue Boc-Asp-FMK with fluoromethylketone residuum was more than 13 times less toxic. Our results further indicated that toxicity of Boc-Asp-CMK might arise from its interference with mitochondrial metabolism.
Authors:
Ivo Frydrych; Petr Mlejnek; Petr Dolezel; Vassilis Zoumpourlis; Petra Krumpochova
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-03-04
Journal Detail:
Title:  Toxicology in vitro : an international journal published in association with BIBRA     Volume:  22     ISSN:  0887-2333     ISO Abbreviation:  Toxicol In Vitro     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-06-16     Completed Date:  2008-08-29     Revised Date:  2009-04-10    
Medline Journal Info:
Nlm Unique ID:  8712158     Medline TA:  Toxicol In Vitro     Country:  England    
Other Details:
Languages:  eng     Pagination:  1356-60     Citation Subset:  IM    
Affiliation:
Department of Biology, Faculty of Medicine, Palacky University, Hnevotinska 3, Olomouc 77515, Czech Republic.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Chloromethyl Ketones / pharmacology*
Apoptosis / drug effects*
Caspase 3 / antagonists & inhibitors*,  metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Humans
Oxygen Consumption / drug effects
U937 Cells / enzymology,  pathology
Chemical
Reg. No./Substance:
0/Amino Acid Chloromethyl Ketones; 0/Enzyme Inhibitors; 0/N-tert-butyloxycarbonyl-aspartyl (benzyl)chloromethylketone; 0/butyloxycarbonyl-aspartyl-fluoromethyl ketone; EC 3.4.22.-/Caspase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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