The histone deacetylase inhibitor FK228 distinctly sensitizes the human leukemia cells to retinoic acid-induced differentiation.
FK228 (depsipeptide) is a novel histone deacetylase inhibitor (HDACI) that has shown therapeutical efficacy in clinical trials for malignant lymphoma. In this article, we examined in vitro effects of FK228 on human leukemia cell lines, NB4 and HL-60. FK228 alone (0.2-1 ng/mL) inhibited leukemia cell growth in a dose-dependent manner and induced death by apoptosis. FK228 had selective differentiating effects on two cell lines when used for 6 h before induction of granulocytic differentiation by retinoic acid (RA) or in combination with RA. These effects were accompanied by a time- and dose-dependent histone H4 hyper-acetylation or histone H3 dephosphorylation and alterations in DNA binding of NF-kappaB in association with cell death and differentiation. Pifithrin-alpha (PFT), an inhibitor of p53 transcriptional activity, protected only NB4 cells with functional p53 from FK228-induced apoptosis and did not interfere with antiproliferative activity in p53-negative HL-60 cells. In NB4 cells, PFT inhibited p53 binding to the p21 (Waf1/Cip1) promotor and induced DNA binding of NF-kappaB leading to enhanced cell survival. Thus, beneficial effects of FK228 on human promyelocytic leukemia may be exerted through the induction of differentiation or apoptosis via histone modification and selective involvement of transcription factors, such as NF-kappaB and p53.
Savickiene
Jurate
J
Department of Developmental Biology, Institute of Biochemistry, LT-08662 Vilnius, Lithuania. jurate_savickiene@yahoo.com
Treigyte
Grazina
G
Borutinskaite
Veronika
V
Navakauskiene
Ruta
R
Magnusson
Karl-Eric
KE
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014212:Tretinoin / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D006131:Growth Inhibitors; D056572:Histone Deacetylase Inhibitors; D014212:Tretinoin; C087123:romidepsin