Peroxisome proliferator-activated receptor gamma-dependent activity of indole ring-substituted 1,1-bis(3'-indolyl)-1-(p-biphenyl)methanes in cancer cells.
OBJECTIVE
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.
Guo
Jingjing
J
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
Chintharlapalli
Sudhakar
S
Lee
Syng-ook
SO
Cho
Sung Dae
SD
Lei
Ping
P
Papineni
Sabitha
S
Safe
Stephen
S
D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014162:Transfection
C505817:1,1-bis(3'-indolyl)-1-(4-biphenyl)methane; C493956:CDKN1A protein, human; D051242:Caveolin 1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma