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Antileukemic activity of combined epigenetic agents, DNMT inhibitors zebularine and RG108 with HDAC inhibitors, against promyelocytic leukemia HL-60 cells

Abstract

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 all trans 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.

Abbreviations

AcH4:

acetylated histone H4

APL:

acute promyelocytic leukemia

DMSO:

dimethyl sulfoxide

DNMT:

DNA methyltransferase

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

H3K4me3:

trimethyl histone H4 methylated at lysine 4 (K4)

HDAC:

histone deacetylase

HPR:

horseradish peroxidase

NBT:

nitro blue tetrazolium

PB:

sodium phenyl butyrate

PBS:

phosphate-buffered saline

PE:

phycoerythrin

PI:

propidium iodide

zebularine:

1-(β-D-ribofuranosyl)-2(1-H)-pyrimidone

PMA:

phorbol myristate acetate

RA:

all-trans retinoic acid

RG108:

2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl) propanoic acid

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Savickiene, J., Treigyte, G., Borutinskaite, VV. et al. Antileukemic activity of combined epigenetic agents, DNMT inhibitors zebularine and RG108 with HDAC inhibitors, against promyelocytic leukemia HL-60 cells. Cell Mol Biol Lett 17, 501–525 (2012). https://doi.org/10.2478/s11658-012-0024-5

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Key words

  • HL-60
  • Differentiation
  • RG108
  • Zebularine
  • HDAC inhibitors
  • E-cadherin
  • Histones