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Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite

A S Belzacq1, C El Hamel, H L Vieira

  • 1CNRS-UMR6022, Université de Technologie de Compiègne, BP 20529, F-60205 Compiègne, France.

Oncogene
|December 26, 2001
PubMed

Insights

Three chemotherapy agents trigger apoptosis by inducing mitochondrial membrane permeabilization (MMP). The adenine nucleotide translocator (ANT) is a key target, with distinct interactions for lonidamine, arsenite, and CD437, revealing varied mechanisms of cell death.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Many experimental chemotherapeutics induce apoptosis via mitochondrial membrane permeabilization (MMP).
  • Understanding the precise molecular targets and mechanisms of these agents is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the role of the adenine nucleotide translocator (ANT) in MMP induced by lonidamine, arsenite, and CD437.
  • To elucidate the distinct mechanisms by which these agents trigger apoptosis and identify potential therapeutic vulnerabilities.

Main Methods:

  • Utilized cells overexpressing vMIA (an ANT-interacting protein) to assess protection against MMP.
  • Performed cell-free assays using ANT proteoliposomes and synthetic lipid bilayers to study direct interactions.
  • Manipulated mitochondrial bioenergetics by inhibiting glycolysis and F(0)F(1)ATPase to modulate drug sensitivity.

Main Results:

  • vMIA overexpression conferred significant protection against lonidamine, arsenite, and CD437-induced apoptosis.
  • Lonidamine, arsenite, and CD437 directly permeabilized ANT proteoliposomes in a ligand-dependent manner (ATP/ADP inhibition).
  • These agents formed distinct ANT channels with varying conductance levels, and their cytotoxic effects were differentially modulated by bioenergetic status.

Conclusions:

  • The adenine nucleotide translocator (ANT) is a direct molecular target for lonidamine, arsenite, and CD437.
  • These compounds exhibit a heterogeneous mode of action, impacting ANT function and cellular apoptosis through distinct pathways.
  • Targeting ANT and understanding cellular bioenergetics offers novel strategies for cancer chemotherapy.

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