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, trifluoromethyl (DIM-C-pPhCF(3)) or phenyl (DIM-C-pPhC(6)H(5)) group activate peroxisome proliferator-activated receptor gamma (PPAR gamma) 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-CpPhC6H5 on their activity as PPAR gamma agonists. Methods Various substituted C-DIM analogs were used to investigate their growth-inhibitory activities and activation of PPAR gamma-mediated transactivation in colon and pancreatic cancer cells. Their structure-dependent induction of putative PPAR gamma-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 PPAR gamma 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-CpPhC6H5 and indole ring-substituted analogs are selective PPAR gamma modulators.