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Research Articles: Therapeutics, Targets, and Development

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

¹ Institute of Biosciences and Technology, Texas A&M University Health Science Center; ² Department of Internal Medicine, Baylor College of Medicine, Houston, Texas; ³ Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonbuk, South Korea; ⁴ M. D. Anderson Cancer Center of Florida; ⁵ Orlando Regional Healthcare, Department of Pathology, Orlando, Florida; and ⁶ Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas

Requests for reprints: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Veterinary Research Building 410, College Station, TX 77843-4466. Phone: 979-845-5988; Fax: 979-862-4929. E-mail: ssafe{at}cvm.tamu.edu

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 G₀-G₁- 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. [Mol Cancer Ther 2008;7(7):2109–20]

Grant support: NIH grants ES09106 and CA112337, Chonbuk National University, and Texas Agricultural Experiment Station.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S.D. Cho and S. Chintharlapalli contributed equally to this article.

Received 11/20/07; revised 4/ 3/08; accepted 4/24/08.