Entinostat, a Novel Histone Deacetylase Inhibitor Is Active in B-cell Lymphoma and Enhances the Anti-Tumour Activity of Rituximab and Chemotherapy Agents

Br J Haematol. 2015 May;169(4):506-19. doi: 10.1111/bjh.13318. Epub 2015 Feb 23.


Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma-bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma.

Keywords: entinostat; histone deacetylase inhibitors; lymphoma; rituximab.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Murine-Derived / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / pharmacology*
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytarabine / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Male
  • Mice
  • Mice, SCID
  • Pyrazines / pharmacology
  • Pyridines / pharmacology*
  • Rituximab
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / metabolism


  • Antibodies, Monoclonal, Murine-Derived
  • BCL2L1 protein, human
  • Benzamides
  • Boronic Acids
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histone Deacetylase Inhibitors
  • Pyrazines
  • Pyridines
  • bcl-X Protein
  • Cytarabine
  • entinostat
  • Rituximab
  • Bortezomib