title: 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes induce apoptosis and inhibit renal cell carcinoma growth.
abstract: OBJECTIVE
  1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes [methylene-substituted diindolylmethanes (C-DIM)] containing p-trifluoromethyl, p-t-butyl, and p-phenyl substituents activate peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibit growth of several different cancer cell lines through receptor-dependent and receptor-independent pathways. The purpose of this study is to investigate the anticancer activity of these compounds in renal cell carcinoma.
  
  
  METHODS
  The anticancer activity of the p-t-butyl-substituted C-DIM compound (DIM-C-pPhtBu) was investigated in ACHN and 786-0 renal cell carcinoma cell lines and in an orthotopic model for renal carcinogenesis using ACHN cells injected directly into the kidney.
  
  
  RESULTS
  PPARgamma is overexpressed in ACHN cells and barely detectable in 786-0 cells, and treatment with DIM-C-pPhtBu induces proteasome-dependent degradation of cyclin D1 and variable effects on p21 and p27 expression in both cell lines. DIM-C-pPhtBu also induced several common proapoptotic responses in ACHN and 786-0 cells, including increased expression of nonsteroidal anti-inflammatory drug-activated gene-1 and endoplasmic reticulum stress, which activates death receptor 5 and the extrinsic pathway of apoptosis. Activation of these responses was PPARgamma independent. In addition, DIM-C-pPhtBu (40 mg/kg/d) also inhibited tumor growth in an orthotopic mouse model for renal carcinogenesis, and this was accompanied by induction of apoptosis in renal tumors treated with DIM-C-pPhtBu but not in tumors treated with the corn oil vehicle (control).
  
  
  CONCLUSIONS
  DIM-C-pPhtBu and related compounds are cytotoxic to renal cancer cells and activate multiple proapoptotic and growth-inhibitory pathways. The results coupled with in vivo anticancer activity show the potential of DIM-C-pPhtBu and related C-DIMs for clinical treatment of renal adenocarcinoma.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: York
authors.forename: Maen
authors.initials: M
authors.lastname: Abdelrahim
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Chintharlapalli
authors.forename: Salina D
authors.initials: SD
authors.lastname: Lucero
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000378:metabolism*; D008697:Methane / Q000737:chemistry; D051379:Mice; D047495:PPAR gamma / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; D000970:Antineoplastic Agents; D007211:Indoles; D047495:PPAR gamma; D008697:Methane