Journal
CANCER RESEARCH
Volume 66, Issue 1, Pages 412-418Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-05-2755
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Funding
- NCI NIH HHS [CA112337, 5P50CA091846-03] Funding Source: Medline
- NIEHS NIH HHS [ES09106] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA112337, P50CA091846] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES009106] Funding Source: NIH RePORTER
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1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF(3)), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC(6)H(5)) substituents have been identified as a new class of peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists that exhibit antitumorigenic activity. The PPAR gamma-active C-DIMs have not previously been studied against bladder cancer. We investigated the effects of the PPAR gamma-active C-DIMs on bladder cancer cells in vitro and bladder tumors in vivo. In this study, the PPAR gamma-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 mu mol/L, respectively. In the less responsive KU7 cells, the PPAR gamma agonists induced caveolin-1 and p21 expression but no changes in cyclin D1 or p27; in 253J-BV cells, the PPAR gamma 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 gamma agonists was significantly down-regulated after cotreatment with the PPAR gamma 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-pPhCF3 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.
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