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Research Articles: Therapeutics

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPAR-dependent and PPAR-independent pathways

Departments of ¹ Biochemistry and Biophysics and ² Physiology and Pharmacology, Texas A&M University, College Station, Texas and ³ Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas

Requests for reprints: Stephen Safe, Department of 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

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing p-trifluoromethyl, t-butyl, and phenyl [1,1-bis(3'-indolyl)-1-(p-phenyl)methane (DIM-C-pPhC₆H₅)] substituents induce peroxisome proliferator-activated receptor (PPAR)–mediated transactivation in SW480 colon cancer cells. These PPAR-active compounds also inhibit cell proliferation and modulate some cell cycle proteins. At concentrations from 2.5 to 7.5 µmol/L, the PPAR agonists induce caveolin-1 and phosphorylation of Akt and cotreatment with the PPAR antagonist GW9662 inhibited the induction response. In contrast, higher concentrations (10 µmol/L) of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing 1,1-bis(3'-indolyl)-1-(p-trifluoromethyl)methane and DIM-C-pPhC₆H₅ induce apoptosis, which is PPAR independent. This was accompanied by loss of caveolin-1 induction but induction of proapoptotic nonsteroidal anti-inflammatory drug activated gene-1. In athymic nude mice bearing SW480 cell xenografts, DIM-C-pPhC₆H₅ inhibits tumor growth at doses of 20 and 40 mg/kg/d and immunohistochemical staining of the tumors showed induction of apoptosis and nonsteroidal anti-inflammatory drug activated gene-1 expression. Thus, the indole-derived PPAR-active compounds induce both receptor-dependent and receptor-independent responses in SW480 cells, which are separable over a narrow range of concentrations. This dual mechanism of action enhances their antiproliferative and anticancer activities. [Mol Cancer Ther 2006;5(5):1362–70]

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Received 1/ 3/06; revised 2/ 2/06; accepted 3/17/06.

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