Indole-3-carbinol-induced death in cancer cells involves EGFR downregulation and is exacerbated in a 3D environment

Apoptosis. 2006 May;11(5):799-812. doi: 10.1007/s10495-006-5877-5.


Indole-3-carbinol (I3C) is a promising anticancer dietary compound, which inhibits breast cancer in animal models. The objective of the current study was to characterize I3C-induced cell death in a panel of human breast tumorigenic cells (MCF7, MDA-MB-468, MDA-MB-231 and HBL100) in comparison with normal fibroblasts. Since epithelial cells are protected from cell death by a three-dimensional environment, 3D cell culture (collagen I gel and spheroids) was employed to investigate susceptibility to I3C. Cell viability in the presence of 256 microM I3C, a concentration close to the physiologically achievable range, was in the order fibroblasts = HBL100>MDA-MB-231>MCF7>MDA-MB-468 in monolayer culture. However, 3D culture conditions increased the susceptibility of MCF7 and MDA-MB-468 cancer cells towards I3C. I3C induced cell death in breast cancer MCF7, MDA-MB-468 and MDA-MB-231 cells via the mitochondrial apoptotic pathway. I3C significantly reduced levels of epidermal growth factor receptor (EGFR) in MDA-MB-468 after 6 h and in MDA-MB-231 and HBL100 cells after 30 h. Downregulation of EGFR in MDA-MB468 and MDA-MB-231 cells using an EGFR inhibitor resulted in apoptosis. EGFR modulation using EGF or an EGFR inhibitor markedly influenced viability and response to I3C in MDA-MB-468 cells in 3D conditions. EGFR expression was modulated by 3D conditions. Therefore, I3C-induced EGFR reduction in these cells is likely to be responsible for I3C-induced apoptosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analysis
  • Apoptosis / drug effects*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Caspase 3
  • Caspase 7
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Estrogen Antagonists / pharmacology*
  • Female
  • Fibroblasts / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Indoles / pharmacology*
  • Quinazolines / pharmacology
  • Time Factors


  • Caspase Inhibitors
  • Estrogen Antagonists
  • Indoles
  • Quinazolines
  • Adenosine Triphosphate
  • indole-3-carbinol
  • ErbB Receptors
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 7
  • Caspases
  • 4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline