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Entinostat, a novel histone deacetylase inhibitor is active in B‐cell lymphoma and enhances the anti‐tumour activity of rituximab and chemotherapy agents
Author(s) -
Frys Sarah,
Simons Zachary,
Hu Qiang,
Barth Matthew J.,
Gu Juan J.,
Mavis Cory,
Skitzki Joseph,
Song Liu,
Czuczman Myron S.,
HernandezIlizaliturri Francisco J.
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13318
Subject(s) - rituximab , lymphoma , cancer research , bortezomib , histone deacetylase inhibitor , histone deacetylase , pharmacology , medicine , cytarabine , multiple myeloma , immunology , chemistry , histone , myeloid leukemia , biochemistry , gene
Summary Histone deacetylases ( HDAC s) 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 ( BCL 2L1) levels and induced apoptosis in cells. In RSCL and RRCL , entinostat induced p21 ( CDKN 1A) 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 CD 20 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.