Purpose: 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 g (PPARg) 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

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... ticancer 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: PPARg is overexpressed in ACHN cells and barely detectable in 786-0 cells, and treatment with DIM-C-pPhtBu induces proteasome-dependent degradation of cyclin D1and variable effects on p21and 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-1and endoplasmic reticulum stress, which activates death receptor 5 and the extrinsic pathway of apoptosis. Activation of these responses was PPARg 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.