1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes decrease mitochondrial membrane potential and induce apoptosis in endometrial and other cancer cell lines

Mol Carcinog. 2008 Jul;47(7):492-507. doi: 10.1002/mc.20407.

Abstract

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes, containing p-t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC(6)H(5)) substituents, are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists; however, DIM-C-pPhtBu-induced growth inhibition and cell death in human HEC1A endometrial cancer cells is PPARgamma-independent. DIM-C-pPhtBu decreased mitochondrial membrane potential (MMP) and promoted the release of cytochrome c and caspase activation and nuclear uptake of endonuclease G leading to apoptosis of HEC1A cells. DIM-C-pPhtBu specifically targeted the mitochondrial permeability transition pore complex (PTPC) because the DIM-C-pPhtBu-induced pro-apoptotic responses were inhibited by atractyloside (Atra), a compound that specifically interacts with the inner mitochondrial membrane adenine nucleotide transport (ANT) proteins. At the dose of Atra used in this study (300 microM), this compound alone did not alter the PTPC but inhibited the mitochondriotoxic effects of DIM-C-pPhtBu. DIM-C-pPhtBu/DIM-C-pPhC(6)H(5) and Atra also differentially affected the ability of eosin-5-maleimide (EMA) to alkylate Cys160 in the ANT protein and Atra, but not DIM-C-pPhtBu, inhibited the exchange of ATP/ADP in isolated mitochondria suggesting that these pharmacophores act on different sites on the ANT protein. Results of this study show that the receptor-independent proapoptotic activity of DIM-C-pPhtBu and DIM-C-pPhC(6)H(5) were related to novel mitochondriotoxic activities involving inner mitochondrial ANT proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotide Translocator 1 / antagonists & inhibitors
  • Adenine Nucleotide Translocator 1 / metabolism
  • Adenosine Triphosphate / metabolism
  • Alkylation
  • Apoptosis / drug effects*
  • Atractyloside / pharmacology
  • Blotting, Northern
  • Blotting, Western
  • Caspases / metabolism
  • Cell Proliferation / drug effects
  • Cytochromes c / metabolism
  • Endometrial Neoplasms / drug therapy
  • Endometrial Neoplasms / metabolism
  • Endometrial Neoplasms / pathology*
  • Enzyme Activation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Indoles / pharmacology*
  • Membrane Potential, Mitochondrial / drug effects*
  • PPAR gamma / agonists*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • 1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane
  • Adenine Nucleotide Translocator 1
  • Indoles
  • PPAR gamma
  • Atractyloside
  • Adenosine Triphosphate
  • Cytochromes c
  • Caspases