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.
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.
Kassouf
Wassim
W
Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Chintharlapalli
Sudhakar
S
Abdelrahim
Maen
M
Nelkin
Gina
G
Safe
Stephen
S
Kamat
Ashish M
AM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D051242:Caveolin 1 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; C492909:1,1-bis(3'-indolyl)-1-(4-trifluoromethylphenyl)methane; D051242:Caveolin 1; D018797:Cell Cycle Proteins; D007211:Indoles; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone