1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes induce apoptosis and inhibit renal cell carcinoma growth.

Abstract

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 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.

• Authors: Melissa York, Maen Abdelrahim, Sudhakar Chintharlapalli, Salina D Lucero, Stephen Safe
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 22 Pt 1 Pg. 6743-52 (Nov 15 2007) ISSN: 1078-0432 [Print] United States
• PMID: 18006776 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane
• Antineoplastic Agents
• Indoles
• PPAR gamma
• Methane

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma, Renal Cell (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Indoles (chemistry, pharmacology)
• Kidney Neoplasms (metabolism)
• Methane (chemistry)
• Mice
• PPAR gamma (analysis, antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays