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A Novel Ring-Substituted Diindolylmethane,1,1-Bis[3'-(5-Methoxyindolyl)]-1-(p-t-Butylphenyl) Methane, Inhibits Extracellular Signal-Regulated Kinase Activation and Induces Apoptosis in Acute Myelogenous Leukemia

Departments of ¹ Blood and Marrow Transplantation and ² Leukemia, University of Texas M.D. Anderson Cancer Center; ³ Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas; ⁴ Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina; and ⁵ Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas

Requests for reprints: Marina Konopleva, Department of Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Unit 448, 1400 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1628; Fax: 713-794-4747; E-mail: mkonople{at}mdanderson.org.

We investigated the antileukemic activity and molecular mechanisms of action of a newly synthesized ring-substituted diindolylmethane derivative, 1,1-bis[3'-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane (DIM #34), in acute myelogenous leukemia (AML) cells. DIM #34 inhibited AML cell growth via the induction of apoptosis and abrogated clonogenic growth of primary AML samples. Exposure to DIM #34 induced loss of mitochondrial inner transmembrane potential, release of cytochrome c into the cytosol, and caspase activation. Bcl-2–overexpressing, Bax knockout, and caspase-9–deficient cells were partially resistant to cell death, suggesting the involvement of the intrinsic apoptotic pathway. Furthermore, DIM #34 transiently inhibited the phosphorylation and activity of the extracellular signal-regulated kinase and abrogated Bcl-2 phosphorylation. Because other methylene-substituted diindolylmethane analogues have been shown to transactivate the nuclear receptor peroxisome proliferator-activated receptor (PPAR), we studied the role of PPAR in apoptosis induction. Cotreatment of cells with a selective PPAR antagonist or with retinoid X receptor and retinoic acid receptor ligands partially modulated apoptosis when combined with DIM #34, suggesting PPAR receptor-dependent and receptor-independent cell death. Together, these findings suggest that diindolylmethanes are a new class of compounds that selectively induce apoptosis in AML cells through the modulation of the extracellular signal-regulated kinase and PPAR signaling pathways.

Key Words: Diindolylmethane • AML • apoptosis • PPAR • ERK

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