BH3‐domain mimetic compound BH3I‐2′ induces rapid damage to the inner mitochondrial membrane prior to the cytochrome c release from mitochondria

Publisher Website
Google Scholar
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.