1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane activates Nur77-independent proapoptotic responses in colon cancer cells

Mol Carcinog. 2008 Apr;47(4):252-63. doi: 10.1002/mc.20378.


1,1-Bis(3'-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH(3)) is a methylene-substituted diindolylmethane (C-DIM) analog that activates the orphan receptor nerve growth factor-induced-Balpha (NGFI-Balpha, Nur77). RNA interference studies with small inhibitory RNA for Nur77 demonstrate that DIM-C-pPhOCH(3) induces Nur77-dependent and -independent apoptosis, and this study has focused on delineating the Nur77-independent proapoptotic pathways induced by the C-DIM analog. DIM-C-pPhOCH(3) induced caspase-dependent apoptosis in RKO colon cancer cells through decreased mitochondrial membrane potential which is accompanied by increased mitochondrial bax/bcl-2 ratios and release of cytochrome c into the cytosol. DIM-C-pPhOCH(3) also induced phosphatidylinositol-3-kinase-dependent activation of early growth response gene-1 which, in turn, induced expression of the proapoptotic nonsteroidal anti-inflammatory drug-activated gene-1 (NAG1) in RKO and SW480 colon cancer cells. Moreover, DIM-C-pPhOCH(3) also induced NAG-1 expression in colon tumors in athymic nude mice bearing RKO cells as xenografts. DIM-C-pPhOCH(3) also activated the extrinsic apoptosis pathway through increased phosphorylation of c-jun N-terminal kinase which, in turn, activated C/EBP homologous transcription factor (CHOP) and death receptor 5 (DR5). Thus, the effectiveness of DIM-C-pPhOCH(3) as a tumor growth inhibitor is through activation of Nur77-dependent and -independent pathways.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Growth Inhibitors / pharmacology
  • Humans
  • Indoles / pharmacology*
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Steroid / metabolism
  • Receptors, Steroid / physiology*
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*


  • 1,1-bis(3'-indolyl)methane
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Growth Inhibitors
  • Indoles
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors