Journal
CANCER RESEARCH
Volume 65, Issue 7, Pages 2890-2898Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-04-3781
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Funding
- NCI NIH HHS [CA100632, CA55164, CA19639, CA16654] Funding Source: Medline
- NIEHS NIH HHS [ES09106] Funding Source: Medline
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We investigated the antileukentic 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 (PPAR gamma), we studied the role of PPAR gamma in apoptosis induction. Cotreatment of cells with a selective PPAR gamma antagonist or with retinoid X receptor and retinoic acid receptor ligands partially modulated apoptosis when combined with DIM #34, suggesting PPAR gamma 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 gamma signaling pathways.
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