1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit proliferation of estrogen receptor-negative breast cancer cells by activation of multiple pathways

Breast Cancer Res Treat. 2008 May;109(2):273-83. doi: 10.1007/s10549-007-9648-y. Epub 2007 Jul 12.


1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing para-trifluoromethyl (DIM-C-pPhCF(3)), t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC(6)H(5)) groups are methylene-substituted diindolylmetyhanes (C-DIMs) that activate peroxisome proliferator-activated receptor gamma (PPARgamma) in estrogen receptor alpha-negative MDA-MB-231 and MDA-MB-453 breast cancer cells. C-DIMs inhibit breast cancer cell proliferation; however, inhibition of G(0)/G(1) to S phase progression and cyclin D1 downregulation was observed in MDA-MB-231 but not MDA-MB-453 cells. Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a transforming growth factor beta-like peptide, was also induced by these compounds, and the response was dependent on cell-context dependent activation of kinase pathways. However, inhibition of cell growth, induction of NAG-1 and activation of kinases by C-DIMs were not inhibited by PPARgamma antagonists. Despite the induction of NAG-1 and downregulation of the antiapoptotic protein survivin by C-DIMs in both MDA-MB-231 and MDA-MB-453 cells, apoptotic cell death was not observed. Nevertheless, the cytotoxicity of C-DIMs in vitro was complemented by inhibition of tumor growth in athymic nude mice bearing MDA-MB-231 cells as xenografts and treated with DIM-C-pPhC(6)H(5) (40 mg/kg/day). The growth inhibition of tumors derived from highly aggressive MDA-MB-231 cells suggests a potential role for the C-DIM compounds in the clinical treatment of ER-negative breast cancer.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cytokines / drug effects
  • Cytokines / metabolism
  • Enzyme Activation / drug effects
  • Female
  • Flow Cytometry
  • Growth Differentiation Factor 15
  • Humans
  • Indoles / pharmacology*
  • Mice
  • Mice, Nude
  • PPAR gamma / antagonists & inhibitors
  • Protein Kinases / drug effects
  • Protein Kinases / metabolism
  • Receptors, Estrogen / metabolism
  • Signal Transduction / drug effects*
  • Transfection
  • Xenograft Model Antitumor Assays


  • 1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane
  • Antineoplastic Agents
  • Cytokines
  • GDF15 protein, human
  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • Indoles
  • PPAR gamma
  • Receptors, Estrogen
  • Protein Kinases