Journal
PHARMACEUTICAL RESEARCH
Volume 32, Issue 3, Pages 779-792Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-013-1231-0
Keywords
cancer; HDAC inhibitor; natural killer cells; NKG2D; NKG2D ligands
Funding
- Brenda and Howard Johnson Fund
- Physician Scientist Program of MD Anderson Cancer Center
- Sunbeam Foundation
- National Natural Science Foundation of China [81071858, 81273216]
- Innovation Program of Shanghai Municipal Education Commission [11ZZ105]
- NCI [CA16672]
- NCRR of the NIH [P40RR017447]
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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.
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