1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes are peroxisome proliferator-activated receptor gamma agonists but decrease HCT-116 colon cancer cell survival through receptor-independent activation of early growth response-1 and nonsteroidal anti-inflammatory drug-activated gene-1.

Abstract

1,1-Bis-(3'-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC6H5) substituents decrease survival of HCT-116 colon cancer cells and activate peroxisome proliferator-activated receptor (PPAR) gamma in this and other cancer cell lines. These PPARgamma-active compounds had minimal effects on expression of cell cycle proteins and did not induce caveolin-1 in HCT-116 cells. However, these compounds induced nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) and apoptosis in HCT-116 cells, and in time-course studies, the PPARgamma agonists maximally induced early growth response-1 (Egr-1) protein within 2 h, whereas a longer time course was observed for induction of NAG-1 protein. These data, coupled with deletion and mutation analysis of both the Egr-1 and NAG-1 gene promoters, indicate that activation of NAG-1 by these compounds was dependent on prior induction of Egr-1, and induction of these responses was PPARgamma-independent. Results of kinase inhibitor studies also demonstrated that activation of Egr-1/NAG-1 by methylene-substituted diindolylmethanes (C-DIMs) was phosphatidylinositol 3-kinase-dependent, and this represents a novel receptor-independent pathway for C-DIM-induced growth inhibition and apoptosis in colon cancer cells.

• Authors: Sudhakar Chintharlapalli, Sabitha Papineni, Seung Joon Baek, Shengxi Liu, Stephen Safe
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 68 Issue 6 Pg. 1782-92 (Dec 2005) ISSN: 0026-895X [Print] United States
• PMID: 16155208 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1,1-bis(3'-indolyl)-1-(4-biphenyl)methane
• 1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane
• 1,1-bis(3'-indolyl)-1-(4-trifluoromethylphenyl)methane
• Cytokines
• EGR1 protein, human
• Early Growth Response Protein 1
• GDF15 protein, human
• Growth Differentiation Factor 15
• Indoles
• PPAR gamma
• Phosphatidylinositol 3-Kinases

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Cytokines (genetics)
• Early Growth Response Protein 1 (genetics)
• Gene Expression Regulation (drug effects)
• Growth Differentiation Factor 15
• Humans
• Indoles (pharmacology)
• PPAR gamma (agonists)
• Phosphatidylinositol 3-Kinases
• Promoter Regions, Genetic