Peroxisome proliferator-activated receptor γ-dependent activity of indole ring-substituted 1,1-bis(3'-indolyl)-1-(p-biphenyl)methanes in cancer cells

Purpose: 1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) substituted in the phenyl ring with a para-, t-butyl, triiiuoromethyl (DIM-C-pPhCF₃) or phenyl (DIM-C-pPhC₆H₅) group activate peroxisome proliferatoractivated receptor γ (PPARγ) in several cancer cell lines, and DIM-C-pPhCF₃ 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-pPhC₆H₅ on their activity as PPARγ agonists. Methods: Various substituted C-DIM analogs were used to investigate their growth-inhibitory activities and activation of PPARγ-mediated transactivation in colon and pancreatic cancer cells. Their structure-dependent induction of putative PPARγ-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 PPARγ 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-pPhC₆H₅ and indole ring-substituted analogs are selective PPARγ modulators.