Inhibition of bladder tumor growth by 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes: a new class of peroxisome proliferator-activated receptor gamma agonists.

Abstract

1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC6H5) substituents have been identified as a new class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that exhibit antitumorigenic activity. The PPARgamma-active C-DIMs have not previously been studied against bladder cancer. We investigated the effects of the PPARgamma-active C-DIMs on bladder cancer cells in vitro and bladder tumors in vivo. In this study, the PPARgamma-active compounds inhibited the proliferation of KU7 and 253J-BV bladder cancer cells, and the corresponding IC50 values were 5 to 10 and 1 to 5 micromol/L, respectively. In the less responsive KU7 cells, the PPARgamma agonists induced caveolin-1 and p21 expression but no changes in cyclin D1 or p27; in 253J-BV cells, the PPARgamma agonists did not affect caveolin-1, cyclin D1, or p27 expression but induced p21 protein. In KU7 cells, induction of caveolin-1 by each of the PPARgamma agonists was significantly down-regulated after cotreatment with the PPARgamma antagonist GW9662. DIM-C-pPhCF3 (60 mg/kg thrice a week for 4 weeks) inhibited the growth of implanted KU7 orthotopic and s.c. tumors by 32% and 60%, respectively, and produced a corresponding decrease in proliferation index. Treatment of KU7 cells with DIM-C-pPhCF3 also elevated caveolin-1 expression by 25% to 30%, suggesting a role for this protein in mediating the antitumorigenic activity of DIM-C-pPhCF3 in bladder cancer.

• Authors: Wassim Kassouf, Sudhakar Chintharlapalli, Maen Abdelrahim, Gina Nelkin, Stephen Safe, Ashish M Kamat
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 1 Pg. 412-8 (Jan 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16397256 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane
• 1,1-bis(3'-indolyl)-1-(4-trifluoromethylphenyl)methane
• Caveolin 1
• Cell Cycle Proteins
• Indoles
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Caveolin 1 (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Growth Processes (drug effects)
• Humans
• Indoles (administration & dosage, pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• PPAR gamma (agonists)
• Rosiglitazone
• Thiazolidinediones (administration & dosage, pharmacology)
• Urinary Bladder Neoplasms (drug therapy, metabolism, pathology)
• Xenograft Model Antitumor Assays