The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines.

Abstract

Histone deacetylase inhibitors have a potent role in the strategy for the treatment of leukemias. BML-210 (N-(2-Aminophenyl)-N' phenyloctanol diamine) is the novel histone deacetylase inhibitor, and its mechanism of action has not been characterized. In this study, we examined the in vitro effects of BML-210 on the human leukemia cell lines (NB4, HL-60, THP-1, and K562). We found that BML-210 inhibits the growth of all cell lines and promotes apoptosis in a dose- and time-dependent manner. BML-210 alone induces HL-60 and K562 cell differentiation (up to 30%) to granulocytes and erythrocytes, respectively, and in combination with differentiation agents - all-trans retinoic acid and hemin, markedly potentates it. Those treatments cause G1 arrest and histone H4 acetylation, affects transcription factor NF-kappaB and Sp1 binding activity to their consensus sequences, the p21 or the FasL promoters, and influences expression of Sp1, NF-kappaB, p21 and FasL. These findings suggest that BML-210 could be a promising antileukemic agent to induce apoptosis and to modulate differentiation through the modulation of histone acetylation and gene expression.

• Authors: Jurate Savickiene, Veronika-Viktorija Borutinskaite, Grazina Treigyte, Karl-Eric Magnusson, Ruta Navakauskiene
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 549 Issue 1-3 Pg. 9-18 (Nov 07 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16978604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anilides
• Histone Deacetylase Inhibitors
• Histones
• N1-(2-aminophenyl)-N8-phenyloctanediamide
• NF-kappa B
• Transcription Factors
• Tumor Suppressor Protein p53
• Tretinoin
• Histone Deacetylases

Topics

• Acetylation (drug effects)
• Anilides (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Differentiation (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Cytoplasm (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Electrophoretic Mobility Shift Assay
• HL-60 Cells
• Histone Deacetylase Inhibitors
• Histone Deacetylases (metabolism)
• Histones (metabolism)
• Humans
• K562 Cells
• Leukemia (metabolism, pathology)
• NF-kappa B (metabolism)
• Protein Binding (drug effects)
• Time Factors
• Transcription Factors (metabolism)
• Tretinoin (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)