The Narrow-Spectrum HDAC Inhibitor Entinostat Enhances NKG2D Expression Without NK Cell Toxicity, Leading to Enhanced Recognition of Cancer Cells

Autor: Cecele J. Denman, Shiguo Zhu, Dean A. Lee, Dennis P.M. Hughes, Eugenie S. Kleinerman, Ching C. Lau, Stephen Gottschalk, Zehra S. Cobanoglu, Simin Kiany
Rok vydání: 2013
Předmět:
Time Factors
Transcription
Genetic
Pyridines
Pharmaceutical Science
Ligands
Histones
chemistry.chemical_compound
Mice
Inbred NOD
Pharmacology (medical)
Promoter Regions
Genetic
Entinostat
Acetylation
Sarcoma
Up-Regulation
Gene Expression Regulation
Neoplastic
Killer Cells
Natural
NK Cell Lectin-Like Receptor Subfamily K
Benzamides
Colonic Neoplasms
Intercellular Signaling Peptides and Proteins
Molecular Medicine
Biotechnology
Antineoplastic Agents
Mice
Transgenic
chemical and pharmacologic phenomena
Biology
GPI-Linked Proteins
Article
Cell Line
Tumor
MHC class I
Animals
Humans
Pharmacology
Binding Sites
Lymphokine-activated killer cell
Dose-Response Relationship
Drug
Histocompatibility Antigens Class I
Organic Chemistry
NKG2D
Xenograft Model Antitumor Assays
Molecular biology
Coculture Techniques
Histone Deacetylase Inhibitors
chemistry
Cell culture
Cancer cell
Cancer research
biology.protein
Histone deacetylase
Zdroj: Pharmaceutical Research. 32:779-792
ISSN: 1573-904X
0724-8741
DOI: 10.1007/s11095-013-1231-0
Popis: Natural killer (NK) cell cytotoxicity correlates with the ligation of activating receptors (e.g., NKG2D) by their ligands (e.g., MHC class I-related chains [MIC] A and B) on target cells. Histone deacetylase inhibitors (HDACi) at high concentrations inhibit tumor growth and can increase NKG2D ligand expression on tumor targets, but are widely regarded as toxic to NK cells.We investigated the mechanism of entinostat, a benzamide-derivative narrow-spectrum HDACi, in augmenting the cytotoxicity of NK cells against human colon carcinoma and sarcoma by assessing gene and protein expression, histone acetylation, and cytotoxicity in in vitro and murine models.We observed that entinostat dose- and time-dependent increase in MIC expression in tumor targets and NKG2D in primary human NK cells, both correlating with increased acetylated histone 3 (AcH3) binding to associated promoters. Entinostat pretreatment of colon carcinoma and sarcoma cells, NK cells, or both led to enhanced overall cytotoxicity in vitro, which was reversed by NKG2D blockade, and inhibited growth of tumor xenografts. Lastly, we showed decreased expression of MICA and ULBP2 transcription in primary human osteosarcoma.Entinostat enhances NK cell killing of cancer cells through upregulation of both NKG2D and its ligands, suggesting an attractive approach for augmenting NK cell immunotherapy of solid tumors such as colon carcinoma and sarcomas.
Databáze: OpenAIRE
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