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

Rooha Contractor, Ismael J. Samudio, Zeev Estrov, David Harris, James A. McCubrey, Stephen H. Safe, Michael Andreeff, Marina Konopleva

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106 Scopus citations

Abstract

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 γ (PPARγ), we studied the role of PPARγ in apoptosis induction. Cotreatment of cells with a selective PPARγ antagonist or with retinoid X receptor and retinoic acid receptor ligands partially modulated apoptosis when combined with DIM #34, suggesting PPARγ 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 PPARγ signaling pathways.

Original languageEnglish (US)
Pages (from-to)2890-2898
Number of pages9
JournalCancer research
Volume65
Issue number7
DOIs
StatePublished - Apr 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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