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

authors
author list (cited authors)
Contractor, R., Samudio, I. J., Estrov, Z., Harris, D., McCubrey, J. A., Safe, S. H., Andreeff, M., & Konopleva, M.
publication date
2005
published in
keywords
  • U937 Cells
  • HL-60 Cells
  • Extracellular Signal-Regulated MAP Kinases
  • Indoles
  • MAP Kinase Signaling System
  • Leukemia, Myeloid, Acute
  • PPAR Gamma
  • Humans
  • Leukemia, Monocytic, Acute
  • Apoptosis
  • Protein Kinase Inhibitors
  • Acute Disease
  • Jurkat Cells
  • Proto-Oncogene Proteins C-bcl-2
  • Leukemia, Myeloid
  • Caspases
  • Leukemia, Myelomonocytic, Acute
  • Enzyme Activation