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- Title
BH3-domain mimetic compound BH3I-2′ induces rapid damage to the inner mitochondrial membrane prior to the cytochrome c release from mitochondria.
- Authors
Feng, Wan-Yu; Liu, Feng-Ting; Patwari, Yasmeen; Agrawal, Samir G.; Newland, Adrian C.; Jia, Li
- Abstract
Summary. 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 (ΔΨm), 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.
- Subjects
MITOCHONDRIAL membranes; CYTOCHROME c; HEMATOLOGY
- Publication
British Journal of Haematology, 2003, Vol 121, Issue 2, p332
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1046/j.1365-2141.2003.04268.x