A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappaB inhibition in malignant myeloblasts.
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.
Fabre
Claire
C
INSERM, U848, Unit Apoptosis, Cancer and Immunity, Villejuif, France.
Grosjean
Jennifer
J
Tailler
Maximilien
M
Boehrer
Simone
S
Adès
Lionel
L
Perfettini
Jean-Luc
JL
de Botton
Stéphane
S
Fenaux
Pierre
P
Kroemer
Guido
G
D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D042381:Granulocyte Precursor Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D014635:Valproic Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; C012589:trichostatin A; D014635:Valproic Acid; D004248:DNA (Cytosine-5-)-Methyltransferases; D051550:I-kappa B Kinase; D001374:Azacitidine