Inhibition of bladder tumor growth by 1,1-bis(3′-indolyl)-1-(p- substitutedphenyl)methanes: A new class of peroxisome proliferator-activated receptor γ agonists

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 γ (PPARγ) agonists that exhibit antitumorigenic activity. The PPARγ-active C-DIMs have not previously been studied against bladder cancer. We investigated the effects of the PPARγ-active C-DIMs on bladder cancer cells in vitro and bladder tumors in vivo. In this study, the PPARγ-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 μmol/L, respectively. In the less responsive KU7 cells, the PPARγ agonists induced caveolin-1 and p21 expression but no changes in cyclin D1 or p27; in 253J-BV cells, the PPARγ 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 PPARγ agonists was significantly down-regulated after cotreatment with the PPARγ 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.