title: The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines.
abstract: We investigated the cytotoxic interactions of romidepsin, a histone deacetylase inhibitor, and lenalidomide, an immunomodulatory agent, in a T-cell lymphoma preclinical model. Hut-78 and Karpas-299 cells were treated with romidepsin and lenalidomide alone and in combination. The interaction between romidepsin and lenalidomide was evaluated by the Chou-Talalay method, and cell viability and clonogenicity were also evaluated. Apoptosis, reactive oxygen species (ROS) levels, and cell cycle distribution were determined by flow cytometry. ER stress, caspase activation, and the AKT, MAPK/ERK, and STAT-3 pathways were analyzed by Western blot. Combination treatment with romidepsin and lenalidomide had a synergistic effect in Hut-78 cells and an additive effect in Karpas-299 cells at 24 hours and did not decrease the viability of normal peripheral blood mononuclear cells. This drug combination induced apoptosis, increased ROS production, and activated caspase-8, -9, -3 and PARP. Apoptosis was associated with increased hallmarks of ER stress and activation of UPR sensors and was mediated by dephosphorylation of the AKT, MAPK/ERK, and STAT3 pathways.The combination of romidepsin and lenalidomide shows promise as a possible treatment for T-cell lymphoma. This work provides a basis for further studies.
authors.affiliation: a Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cosenza
authors.affiliation: a Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Civallero
authors.affiliation: b Department of Medical and Surgical Sciences for Children and Adults , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiorcari
authors.affiliation: a Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Pozzi
authors.affiliation: a Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marcheselli
authors.affiliation: a Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bari
authors.affiliation: c Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ferri
authors.affiliation: a Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic Clinical and Public Health Medicine , University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sacchi
keywords: Lenalidomide; T-cell lymphoma; romidepsin; synergistic interaction; tumor cell death