Abstract
We studied the cellular and molecular effects of the combination of an anthracycline with 2 different histone deacetylase inhibitors (HDACIs): vorinostat (suberoylanilide hydroxamic acid) and valproic acid (VPA). The 10% inhibitory concentration (IC(10)) of idarubicin was 0.5 nM in MOLT4 and 1.5 nM in HL60 cells. Concentrations above 0.675 microM of vorinostat resulted in at least 80% loss of cell viability in both cell lines. Concentrations of 1.5 to 3 mM of VPA induced 50% to 60% loss in viability in HL60 and 80% in MOLT4 cells. The combination of idarubicin with vorinostat at 0.075 microM or VPA at 0.25 mM resulted in at least an additive loss of cell viability in both lines. Vorinostat (0.35 microM) and VPA (0.25 mM) in combination with idarubicin (0.5 nM) resulted in a significant increase in apoptotic cells in MOLT4 cells. The combination resulted in an increase in histone H3 and H4 acetylation at 24 hours, phosphorylated H2AX, as well as in the induction of p21(CIP1) mRNA. No effect on cell cycle transition was observed. Of importance, the cellular and molecular effects observed were independent of the sequence used. In summary, the combination of an anthracycline with an HDACI should have significant clinical activity in patients with leukemia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Antibiotics, Antineoplastic / pharmacology
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Antibiotics, Antineoplastic / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Cell Cycle / drug effects
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Cell Survival / drug effects
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Gene Expression Regulation, Leukemic / drug effects
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HL-60 Cells
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Histone Deacetylase Inhibitors*
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Histone Deacetylases / metabolism
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Histones / metabolism
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Humans
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Hydroxamic Acids
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Idarubicin / pharmacology
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Idarubicin / therapeutic use
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Leukemia / drug therapy*
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Leukemia / enzymology
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Protein Processing, Post-Translational / drug effects
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RNA, Messenger / biosynthesis
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Valproic Acid / pharmacology
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Valproic Acid / therapeutic use
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Vorinostat
Substances
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Antibiotics, Antineoplastic
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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RNA, Messenger
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Vorinostat
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Valproic Acid
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Histone Deacetylases
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Idarubicin