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.
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.
Contractor
Rooha
R
Department of Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Samudio
Ismael J
IJ
Estrov
Zeev
Z
Harris
David
D
McCubrey
James A
JA
Safe
Stephen H
SH
Andreeff
Michael
M
Konopleva
Marina
M
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D019169:Jurkat Cells; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D020298:U937 Cells
C500672:1,1-bis(3'-(5-methoxyindolyl))-1-(p-t-butylphenyl)indolesmethane; D007211:Indoles; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases