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

Abstract

1,1-Bis(3V -indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF 3 ), p-t-butyl (DIM-CpPhtBu), and phenyl (DIM-C-pPhC 6 H 5 ) substituents have been identified as a new class of peroxisome proliferator-activated receptor ; (PPAR;) agonists that exhibit antitumorigenic activity. The PPAR;-active C-DIMs have not previously been studied against bladder cancer. We investigated the effects of the PPAR;-active C-DIMs on bladder cancer cells in vitro and bladder tumors in vivo. In this study, the PPAR;-active compounds inhibited the proliferation of KU7 and 253J-BV bladder cancer cells, and the corresponding IC 50 values were 5 to 10 and 1 to 5 Mmol/L, respectively. In the less responsive KU7 cells, the PPAR; agonists induced caveolin-1 and p21 expression but no changes in cyclin D1 or p27; in 253J-BV cells, the PPAR; 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 PPAR; agonists was significantly down-regulated after cotreatment with the PPAR; antagonist GW9662. DIM-C-pPhCF 3 (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-pPhCF 3 also elevated caveolin-1 expression by 25% to 30%, suggesting a role for this protein in mediating the antitumorigenic activity of DIM-C-pPhCF 3 in bladder cancer. (Cancer Res 2006; 66(1): 412-8)

1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator–activated receptor–dependent and independent pathways

“…1C. The higher growth inhibitory activity of DIM-C-pPhtBu and related compounds compared with thiazolidinediones has also been observed in bladder, colon, and pancreatic cancer cells (37,38,41).…”

Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-κB and nuclear factor-κB–regulated gene products in IFN-α–sensitive and IFN-α–resistant human bladder cancer cells

“…How curcumin overcomes resistance to IFN-a is unclear, but a previous study showed that this cytokine mediates its apoptotic effects through the induction of TRAIL (34). Similar to curcumin, genistein (derived from soy) and analogues of indole-3-carbinol (derived from cruciferous vegetables) have been shown to suppress the proliferation of bladder cancer cells (35,36). Curcumin has been shown to have no effect on normal cells.…”

“…Whether all of these effects of curcumin are mediated by targeting NF-nB is not clear. Previously, we showed that the indole-3-carbinol analogue DIM can mediate its effects against bladder cancer by targeting peroxisome proliferator-activated receptor-g (36). Curcumin is agonist of peroxisome proliferator-activated receptor-g as well (41).…”

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

“…18 To silence endogenous Nurr1, we used small interfering RNA-oligo targeting Nurr1 purchased from Ambion (Austin, Tex); sense: 5 0 -GGCUUGUAAAUUUACCCAA TT-3 0 , antisense: 5 0 -UUGGGUAAAUUUACAAGCC TT-3 0 . As nontargeting control, Silencer Negative Control small interfering RNA (Ambion) was used.…”

“…Thereafter, for cell viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed as described previously. 18 For migration assay, a modified Boyden Chamber method was used. 19 In brief, 2.5 Â 10 4 cells in 500 lL were seeded into the transwell insert chamber with a filter, and the inserts were placed in the lower chambers filled with 750 lL of RPMI-1640 containing 5% fetal calf serum.…”