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Response of Retinoic Acid‐Resistant KG1 Cells to Combination of Retinoic Acid with Diverse Histone Deacetylase Inhibitors
Author(s) -
Savickiene Jurate,
Treigyte Grazina,
Magnusson KarlEric,
Navakauskiene Ruta
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.04718.x
Subject(s) - retinoic acid , histone deacetylase , chemistry , retinoic acid inducible orphan g protein coupled receptor , retinoic acid receptor beta , histone deacetylase inhibitor , retinoic acid receptor alpha , retinoic acid receptor , pharmacology , cancer research , histone , microbiology and biotechnology , biochemistry , biology , gene
Acute promyelocytic leukemia KG1 cells with t(11;17) PLZF‐RARα respond poorly to the differentiation inducer all‐ trans retinoic acid (RA), and the reason for the RA resistance is the recruitment of histone deacetylase by PLZF‐RARα. Here, we demonstrate that histone deacetylase inhibitors (HDACIs), FK228, BML‐210, phenyl butyrate, and vitamin B3, in different combinations with RA, act as KG1 cell growth inhibitors. Partial differentiation to granulocytes was induced by 3 μmol/L RA, and its combination with HDAC inhibitors did not enhance RA‐induced but potentiated apoptosis. HDACIs induced accumulation of hyperacetylated histone H4. Chromatin immunoprecipitation analysis has revealed phenyl butyrate and its combinations with RA and vitamin B3 cause histone H4 acetylation in the p21 promoter regions corresponding to p53 and/or Sp1 sites. This was coincident with the activation of the transcription factor p53‐binding activity to the p21 promoter in electrophoretic mobility shift assay. The results indicate the possibility of using the combination of agents for therapeutic strategy in RA‐resistant acute myeloid leukemia to produce both differentiation and apoptosis.