Document Detail


BH3-domain mimetic compound BH3I-2' induces rapid damage to the inner mitochondrial membrane prior to the cytochrome c release from mitochondria.
MedLine Citation:
PMID:  12694257     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The Bcl-2 family proteins are major regulators of cell survival and death in human leukaemia. BH3-containing peptides induce apoptosis by binding to the hydrophobic pocket of the anti-apoptotic proteins, such as Bcl-2 or Bcl-XL. A small cell-permeable compound, BH3I-2' (3-iodo-5-chloro-N-[2-chloro-5-((4-chlorophenyl)sulphonyl)phenyl]-2-hydroxybenzamide), has been recently reported to have a function similar to Bak BH3 peptide. BH3I-2' induces apoptosis by disrupting interactions mediated by the BH3 domain, between pro-apoptotic and anti-apoptotic members of the Bcl-2 family. This study found that BH3I-2' induced cytochrome c release from the mitochondrial outer membrane in a Bax-dependent manner and that this correlated with the sensitivity of leukaemic cells to apoptosis. Moreover, it also induced rapid damage to the inner mitochondrial membrane, represented by a rapid collapse of mitochondrial membrane potential (DeltaPsim), prior to the cytochrome c release. This occurred both in whole cells and isolated mitochondria, and was not associated with the sensitivity of cells to BH3I-2'-induced apoptosis. Exogenous Bcl-2 or Bcl-XL neutralized BH3I-2'in vitro and diminished its effect on the inner mitochondrial membrane. Our results indicate that BH3I-2' not only induces cytochrome c release from the outer mitochondrial membrane but also damages the inner mitochondrial membrane, probably by interacting with Bcl-2 family proteins.
Authors:
Wan-Yu Feng; Feng-Ting Liu; Yasmeen Patwari; Samir G Agrawal; Adrian C Newland; Li Jia
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of haematology     Volume:  121     ISSN:  0007-1048     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-04-15     Completed Date:  2003-05-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  England    
Other Details:
Languages:  eng     Pagination:  332-40     Citation Subset:  IM    
Affiliation:
Department of Haematology, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Benzamides / pharmacology
Biomimetic Materials*
Cell Line
Cells, Cultured
Cytochrome c Group / metabolism*
Flow Cytometry
Humans
Intracellular Membranes / drug effects*
Mitochondria / drug effects*,  metabolism
Peptide Fragments
Proto-Oncogene Proteins
Chemical
Reg. No./Substance:
0/3-iodo-5-chloro-N-(2-chloro-5-((4-chlorophenyl)sulphonyl)phenyl)-2-hydroxybenzamide; 0/Bax protein (53-86); 0/Benzamides; 0/Cytochrome c Group; 0/Peptide Fragments; 0/Proto-Oncogene Proteins

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