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Antileukemic activity of combined epigenetic agents, DNMT inhibitors zebularine and RG108 with HDAC inhibitors, against promyelocytic leukemia HL-60 cells.
MedLine Citation:
PMID:  22820861     Owner:  NLM     Status:  Publisher    
DNMT inhibitors are promising new drugs for cancer therapies. In this study, we have observed the antileukemic action of two diverse DNMT inhibitors, the nucleoside agent zebularine and the non-nucleoside agent RG108, in human promyelocytic leukemia (PML) HL-60 cells. Zebularine but not RG108 caused dose- and time-dependent cell growth inhibition and induction of apoptosis. However, co-treatment with either drug at a non-toxic dose and alltrans retinoic acid (RA) reinforced differentiation to granulocytes, while 24 or 48 h-pretreatment with zebularine or RG108 followed by RA alone or in the presence of HDAC inhibitors (sodium phenyl butyrate or BML-210) significantly accelerated and enhanced cell maturation to granulocytes. This occurs in parallel with the expression of a surface biomarker, CD11b, and early changes in histone H4 acetylation and histone H3K4me3 methylation. The application of both drugs to HL-60 cells in continuous or sequential fashion decreased DNMT1 expression, and induced E-cadherin promoter demethylation and reactivation at both the mRNA and the protein levels in association with the induction of granulocytic differentiation. The results confirmed the utility of zebularine and RG108 in combinations with RA and HDAC inhibitors to reinforce differentiation effects in promyelocytic leukemia.
Jurate Savickiene; Grazina Treigyte; Veronika-Viktorija Borutinskaite; Ruta Navakauskiene
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-20
Journal Detail:
Title:  Cellular & molecular biology letters     Volume:  -     ISSN:  1689-1392     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9607427     Medline TA:  Cell Mol Biol Lett     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Mokslininkų 12, Vilnius, LT, 08662, Lithuania.
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