title: Novel HDAC inhibitors exhibit pre-clinical efficacy in lymphoma models and point to the importance of CDKN1A expression levels in mediating their anti-tumor response.
abstract: We investigated the pre-clinical activities of two novel histone deacetylase inhibitors (HDACi), ITF-A and ITF-B, in a large panel of pre-clinical lymphoma models. The two compounds showed a dose-dependent anti-proliferative activity in the majority of cell lines. Gene expression profiling (GEP) of diffuse large B-cell lymphoma (DLBCL) cells treated with the compounds showed a modulation of genes involved in chromatin structure, cell cycle progression, apoptosis, B-cell signaling, and genes encoding metallothioneins. Cell lines showed differences between the concentrations of ITF-A and ITF-B needed to cause anti-proliferative or cytotoxic activity, and cell cycle and apoptosis genes appeared implicated in determining the type of response. In particular, CDKN1A expression was higher in DLBCL cells that, to undergo apoptosis, required a much higher amount of drug than that necessary to induce only an anti-proliferative effect.In conclusion, the two novel HDACi ITF-A and ITF-B demonstrated anti-proliferative activity across different mature B-cell lymphoma cell lines. Basal CDKN1A levels appeared to be important in determining the gap between HDACi concentrations causing cell cycle arrest and those that lead to cell death.
authors: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors: Afua Adjeiwaa
authors: AA
authors: Mensah
authors: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.
authors: Ivo
authors: I
authors: Kwee
authors: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors: Eugenio
authors: E
authors: Gaudio
authors: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors: Andrea
authors: A
authors: Rinaldi
authors: Unit of Lymphoid Malignancies, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy.
authors: Maurilio
authors: M
authors: Ponzoni
authors: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors: Luciano
authors: L
authors: Cascione
authors: Preclinical R&D Department, Italfarmaco S.p.A., Cinisello Balsamo, Milan, Italy.
authors: Gianluca
authors: G
authors: Fossati
authors: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors: Anastasios
authors: A
authors: Stathis
authors: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors: Emanuele
authors: E
authors: Zucca
authors: Preclinical R&D Department, Italfarmaco S.p.A., Cinisello Balsamo, Milan, Italy.
authors: Gianluca
authors: G
authors: Caprini
authors: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors: Francesco
authors: F
authors: Bertoni
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors
keywords: CDKN1A; MYC; NFKB; STAT3; histone deacetylase