| 19823826 |
Guo J, Chintharlapalli S, Lee SO, Cho SD, Lei P, Papineni S, Safe S: Peroxisome proliferator-activated receptor gamma-dependent activity of indole ring-substituted 1,1-bis (3'-indolyl)-1-(p-biphenyl) methanes in cancer cells. Cancer Chemother Pharmacol. 2009 Oct 13.
PURPOSE: 1,1-Bis (3-indolyl)-1-(p-substituted phenyl) methanes (C-DIMs) substituted in the phenyl ring with a para-, t-butyl, trifluoromethyl (DIM-C-pPhCF (3)) or phenyl (DIM-C-pPhC (6) H (5)) group activate peroxisome proliferator-activated receptor gamma (PPARgamma) in several cancer cell lines, and DIM-C-pPhCF (3) also activates the orphan receptor Nur77. In this study, we have examined the effects of 5,5'-dihydroxy, 5,5'-dimethyl, 5,5'-dibromo, 5,5'-dinitro and 5,5'-dimethoxyindole ring-substituted analogs of DIM-C-pPhC (6) H (5) on their activity as PPARgamma agonists. METHODS: Various substituted C-DIM analogs were used to investigate their growth-inhibitory activities and activation of PPARgamma-mediated transactivation in colon and pancreatic cancer cells. Their structure-dependent induction of putative PPARgamma-responsive genes/proteins including p21, KLF-4 and caveolin1 were also determined by Western and Northern blot analysis. RESULTS: Introduction of the 5,5'-dihydroxy and 5,5'-dimethyl substituents enhanced activation of PPARgamma in colon and pancreatic cancer cells. However, activation of p21 in Panc28 pancreatic cancer cells and induction of caveolin-1 and KLF4 in colon cancer cells by the C-DIM compounds were structure- and cell context-dependent. CONCLUSIONS: The results demonstrate that DIM-C-pPhC (6) H (5) and indole ring-substituted analogs are selective PPARgamma modulators. |
12(0,0,1,7) |