A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappaB inhibition in malignant myeloblasts.

Abstract

Malignant myeloblasts arising in high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the constitutive activation of the anti-apoptotic transcription factor NFkappaB. We found that DNA methyltransferase (DNMT) inhibitors (such as azacytidine and 5-aza-2'-deoxycytidine) and histone deacetylase (HDAC) inhibitors (such as trichostatin and valproic acid) efficiently induced apoptosis in the P39 MDS/AML cell line, correlating with an inhibition of NFkappaB (which translocated from the nucleus to the cytoplasm). This effect was obtained rapidly, within a few hours, suggesting that it was not due to epigenetic reprogramming. Indeed, DNMT and HDAC inhibitors reduced the phosphorylation of the NFkappaB-activating kinase IKKalpha/beta, and this effect was also observed in enucleated cells. Finally, circulating myeloblasts from AML patients treated with the DNMT inhibitor 5-aza-2'-deoxycytidine manifested a rapid (2 hours post-treatment) inhibition of NFkappaB and IKKalpha/beta. Altogether, these results indicate that DNMT and HDAC inhibitors can inhibit the constitutive activation of NFkappaB in malignant myeloblasts in vitro and in vivo through a novel mechanism.

• Authors: Claire Fabre, Jennifer Grosjean, Maximilien Tailler, Simone Boehrer, Lionel Adès, Jean-Luc Perfettini, Stéphane de Botton, Pierre Fenaux, Guido Kroemer
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 7 Issue 14 Pg. 2139-45 (Jul 15 2008) ISSN: 1551-4005 [Electronic] United States
• PMID: 18641459 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• NF-kappa B
• trichostatin A
• Valproic Acid
• DNA (Cytosine-5-)-Methyltransferases
• I-kappa B Kinase
• Azacitidine

Topics

• Azacitidine (pharmacology)
• Cell Line, Tumor
• DNA (Cytosine-5-)-Methyltransferases (antagonists & inhibitors)
• Enzyme Inhibitors (pharmacology)
• Female
• Granulocyte Precursor Cells (drug effects, enzymology, metabolism)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• I-kappa B Kinase (metabolism)
• Leukemia, Myeloid, Acute (metabolism, pathology)
• Male
• Middle Aged
• NF-kappa B (antagonists & inhibitors)
• Valproic Acid (pharmacology)