5,5'-Dibromo-bis(3'-indolyl)methane induces Kruppel-like factor 4 and p21 in colon cancer cells.

Abstract

Bis(3'-indolyl)methane (DIM) is a metabolite of the phytochemical indole-3-carbinol, and both compounds exhibit a broad spectrum of anticancer activities. We have developed a series of synthetic symmetrical ring-substituted DIM analogues, including 5,5'-dibromoDIM, which are more potent than DIM as inhibitors of cancer cell and tumor growth. In colon cancer cells, 5,5'-dibromoDIM decreased cell proliferation and inhibited G(0)-G(1)- to S-phase progression, and this was accompanied by induction of the cyclin-dependent kinase inhibitor p21 in HT-29 and RKO colon cancer cells. Mechanistic studies showed that induction of p21 in both RKO (p53 wild-type) and HT-29 (p53 mutant) cells by 5,5'-dibromoDIM was Krüppel-like factor 4 (KLF4) dependent, and induction of p53 in RKO cells was also KLF4 dependent. Analysis of the p21 promoter in p53-dependent RKO cells showed that 5,5'-dibromoDIM activated p21 gene expression through the proximal GC-rich sites 1 and 2, and chromatin immunoprecipitation assays showed that KLF4 and p53 bound to this region of the promoter, whereas in HT-29 cells unidentified upstream cis-elements were required for induction of p21. 5,5'-DibromoDIM (30 mg/kg/d) also inhibited tumor growth and induced p21 in athymic nude mice bearing RKO cells as xenografts, showing that ring-substituted DIM such as 5,5'-dibromoDIM represent a novel class of mechanism-based drugs for clinical treatment of colon cancer.

• Authors: Sung Dae Cho, Sudhakar Chintharlapalli, Maen Abdelrahim, Sabitha Papineni, Shengxi Liu, Jingjing Guo, Ping Lei, Ala Abudayyeh, Stephen Safe
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 7 Pg. 2109-20 (Jul 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18645021 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 5,5'-dibromo-1,1-bis(3'-indolyl)methane
• Cyclin-Dependent Kinase Inhibitor p21
• Indoles
• KLF4 protein, human
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Tumor Suppressor Protein p53

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (pharmacology)
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (metabolism)
• Male
• Mice
• Mice, Nude
• Promoter Regions, Genetic (genetics)
• Protein Binding (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays