1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes induce peroxisome proliferator-activated receptor gamma-mediated growth inhibition, transactivation, and differentiation markers in colon cancer cells.

Abstract

1,1-Bis(3'indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF)), p-t-butyl (DIM-C-pPhtBu), and p-phenyl (DIM-C-pPhC6H5) groups induce peroxisome proliferator-activated receptor gamma (PPARgamma)-mediated transactivation in HT-29, HCT-15, RKO, and SW480 colon cancer cell lines. Rosiglitazone also induces transactivation in these cell lines and inhibited growth of HT-29 cells, which express wild-type PPARgamma but not HCT-15 cells, which express mutant (K422Q) PPARgamma. In contrast, DIM-C-pPhCF3, DIM-C-pPhtBu, and DIM-C-pPhC6H5 inhibited growth of both HT-29 and HCT-15 cells with IC50 values ranging from 1 to 10 micromol/L. Rosiglitazone and diindolylmethane (DIM) analogues did not affect expression of cyclin D1, p21, or p27 protein levels or apoptosis in HCT-15 or HT-29 cells but induced keratin 18 in both cell lines. However, rosiglitazone induced caveolins 1 and 2 in HT-29 but not HCT-15 cells, whereas these differentiation markers were induced by DIM-C-pPhCF3 and DIM-C-pPhC6H5 in both cell lines. Because overexpression of caveolin 1 is known to suppress colon cancer cell and tumor growth, the growth inhibitory effects of rosiglitazone and the DIM compounds are associated with PPARgamma-dependent induction of caveolins.

• Authors: Sudhakar Chintharlapalli, Roger Smith 3rd, Ismael Samudio, Wei Zhang, Stephen Safe
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 17 Pg. 5994-6001 (Sep 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15342379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers, Tumor
• Cell Cycle Proteins
• Indoles
• Receptors, Cytoplasmic and Nuclear
• Thiazolidinediones
• Transcription Factors
• Rosiglitazone
• Methane

Topics

• Apoptosis (drug effects, physiology)
• Biomarkers, Tumor (biosynthesis)
• Cell Cycle Proteins (metabolism)
• Cell Differentiation (drug effects, physiology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Humans
• Indoles (pharmacology)
• Methane (analogs & derivatives, pharmacology)
• Receptors, Cytoplasmic and Nuclear (agonists, biosynthesis, genetics, physiology)
• Rosiglitazone
• Thiazolidinediones (pharmacology)
• Transcription Factors (agonists, biosynthesis, genetics, physiology)
• Transcriptional Activation (drug effects, physiology)