Oncotarget

Research Papers:

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

Afua Adjeiwaa Mensah, Ivo Kwee, Eugenio Gaudio, Andrea Rinaldi, Maurilio Ponzoni, Luciano Cascione, Gianluca Fossati, Anastasios Stathis, Emanuele Zucca, Gianluca Caprini and Francesco Bertoni _

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Oncotarget. 2015; 6:5059-5071. https://doi.org/10.18632/oncotarget.3239

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Abstract

Afua Adjeiwaa Mensah1, Ivo Kwee1,2, Eugenio Gaudio1, Andrea Rinaldi1, Maurilio Ponzoni3, Luciano Cascione1,4, Gianluca Fossati5, Anastasios Stathis4, Emanuele Zucca4, Gianluca Caprini5 and Francesco Bertoni1,4

1 Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland

2 Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland

3 Unit of Lymphoid Malignancies, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy

4 IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

5 Preclinical R&D Department, Italfarmaco S.p.A., Cinisello Balsamo, Milan, Italy

Correspondence:

Francesco Bertoni, email:

Keywords: histone deacetylase, CDKN1A, MYC, NFKB, STAT3

Received: October 08, 2014 Accepted: December 25, 2014 Published: December 30, 2014

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.


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