Selective BH3-mimetics targeting BCL-2, BCL-XL or MCL-1 induce severe mitochondrial perturbations

Biol Chem. 2019 Jan 28;400(2):181-185. doi: 10.1515/hsz-2018-0233.

Abstract

Induction of apoptosis by selective BH3-mimetics is currently investigated as a novel strategy for cancer treatment. Here, we report that selective BH3-mimetics induce apoptosis in a variety of hematological malignancies. Apoptosis is accompanied by severe mitochondrial toxicities upstream of caspase activation. Specifically, the selective BH3-mimetics ABT-199, A-1331852 and S63845, which target BCL-2, BCL-XL and MCL-1, respectively, induce comparable ultrastructural changes including mitochondrial swelling, a decrease of mitochondrial matrix density and severe loss of cristae structure. These shared effects on mitochondrial morphology indicate a similar function of these anti-apoptotic BCL-2 proteins in maintaining mitochondrial integrity and function.

Keywords: BCL-2 proteins; BH3-mimetics; apoptosis; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Caspases / metabolism
  • Enzyme Activation
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Molecular Mimicry*
  • Myeloid Cell Leukemia Sequence 1 Protein / drug effects*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / drug effects*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • bcl-X Protein / drug effects*
  • bcl-X Protein / metabolism

Substances

  • BCL2 protein, human
  • BCL2L1 protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Caspases