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Research Articles: Therapeutics

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator–activated receptor–dependent and independent pathways

¹ Institute of Biosciences and Technology, Texas A&M Health Science Center and ² 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, 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-t-butylphenyl)methane (DIM-C-pPhtBu) is a peroxisome proliferator–activated receptor (PPAR) agonist, and treatment of SKOV3 ovarian cancer cells with this compound (5 µmol/L) inhibits cell proliferation, whereas up to 15 µmol/L rosiglitazone had no effect on cell growth. DIM-C-pPhtBu also inhibits G₀-G₁ to S phase cell cycle progression and this is linked, in part, to PPAR-dependent induction of the cyclin-dependent kinase inhibitor p21. DIM-C-pPhtBu induces PPAR-independent down-regulation of cyclin D1 and we therefore further investigated activation of receptor-independent pathways. DIM-C-pPhtBu also induced apoptosis in SKOV3 cells and this was related to induction of glucose-related protein 78, which is typically up-regulated as part of the unfolded protein response during endoplasmic reticulum (ER) stress. Activation of ER stress was also observed in other ovarian cancer cell lines treated with DIM-C-pPhtBu. In addition, DIM-C-pPhtBu induced CCAAT/enhancer binding protein homologous protein through both ER stress and c-jun NH₂-terminal kinase–dependent pathways, and CCAAT/enhancer binding protein homologous protein activated death receptor 5 and the extrinsic pathway of apoptosis. These results show that DIM-C-pPhtBu inhibits growth and induces apoptosis in ovarian cancer cells through both PPAR-dependent and PPAR-independent pathways, and this complex mechanism of action will be advantageous for future clinical development of these compounds for treatment of ovarian cancer. [Mol Cancer Ther 2006;5(9):2324–38]

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³ S. Chintharlapalli and S. Safe, unpublished results.

Received 4/ 4/06; revised 7/ 3/06; accepted 7/12/06.

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