Abstract
Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.
Keywords:
anticancer agents; drug discovery; epigenetics-based chemotherapy.
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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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Autophagy / drug effects
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Cell Line, Transformed / drug effects
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Cell Line, Tumor
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Cell Survival / drug effects
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DNA Breaks, Double-Stranded / drug effects
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Doxorubicin / pharmacology
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Etoposide / pharmacology
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Histone Deacetylase Inhibitors / chemical synthesis*
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / metabolism*
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Histones / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Mice
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Trehalose / pharmacology
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Tubulin / metabolism
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Vorinostat
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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H2AX protein, human
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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Tubulin
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Vorinostat
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Etoposide
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Doxorubicin
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Trehalose
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Histone Deacetylases