Peroxisome proliferator-activated receptor γ-dependent activity of indole ring-substituted 1,1-bis(3′-indolyl)-1-(p-biphenyl)methanes in cancer cells
Cancer chemotherapy and pharmacology, 2010•Springer
Abstract 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 γ (PPARγ) 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 …
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 γ (PPARγ) 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 …
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-pPhCF3) or phenyl (DIM-C-pPhC6H5) group activate peroxisome proliferator-activated 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.
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