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1,1-bis(3 -indolyl)-1-(p-substitutedphenyl)methanes induce apoptosis and inhibit renal cell carcinoma growth York M; Abdelrahim M; Chintharlapalli S; Lucero SD; Safe SClin Cancer Res 2007[Nov]; 13 (22 Pt 1): 6743-52PURPOSE: 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. EXPERIMENTAL DESIGN: 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.|Animals[MESH]|Antineoplastic Agents/*pharmacology[MESH]|Apoptosis[MESH]|Carcinoma, Renal Cell/*metabolism[MESH]|Cell Line, Tumor[MESH]|Cell Proliferation/drug effects[MESH]|Humans[MESH]|Indoles/chemistry/*pharmacology[MESH]|Kidney Neoplasms/*metabolism[MESH]|Methane/chemistry[MESH]|Mice[MESH]|PPAR gamma/analysis/*antagonists & inhibitors/metabolism[MESH]|Xenograft Model Antitumor Assays[MESH] |
