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Pleiotropic antitumor effects of the pan‐HDAC inhibitor ITF2357 against c‐Myc‐overexpressing human B‐cell non‐Hodgkin lymphomas
Author(s) -
Zappasodi Roberta,
Cavanè Alessandra,
Iorio Marilena V.,
Tortoreto Monica,
Guarnotta Carla,
Ruggiero Giusi,
Piovan Claudia,
Magni Michele,
Zaffaroni Nadia,
Tagliabue Elda,
Croce Carlo M.,
Zunino Franco,
Gianni Alessandro M.,
Di Nicola Massimo
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28852
Subject(s) - raji cell , cancer research , downregulation and upregulation , cell culture , apoptosis , cell cycle , cell growth , biology , cell cycle checkpoint , cell , lymphoma , microbiology and biotechnology , immunology , gene , biochemistry , genetics
Histone deacetylases (HDAC) extensively contribute to the c‐Myc oncogenic program, pointing to their inhibition as an effective strategy against c‐Myc‐overexpressing cancers. We, thus, studied the therapeutic activity of the new‐generation pan‐HDAC inhibitor ITF2357 (Givinostat®) against c‐Myc‐overexpressing human B‐cell non‐Hodgkin lymphomas (B‐NHLs). ITF2357 anti‐proliferative and pro‐apoptotic effects were analyzed in B‐NHL cell lines with c‐Myc translocations (Namalwa, Raji and DOHH‐2), stabilizing mutations (Raji) or post‐transcriptional alterations (SU‐DHL‐4) in relationship to c‐Myc modulation. ITF2357 significantly delayed the in vitro growth of all B‐NHL cell lines by inducing G1 cell‐cycle arrest, eventually followed by cell death. These events correlated with the extent of c‐Myc protein, but not mRNA, downregulation, indicating the involvement of post‐transcriptional mechanisms. Accordingly, c‐Myc‐targeting microRNAs let‐7a and miR‐26a were induced in all treated lymphomas and the cap‐dependent translation machinery components 4E‐BP1, eIF4E and eIF4G, as well as their upstream regulators, Akt and PIM kinases, were inhibited in function of the cell sensitivity to ITF2357, and, in turn, c‐Myc downregulation. In vivo , ITF2357 significantly hampered the growth of Namalwa and Raji xenografts in immunodeficient mice. Noteworthy, its combination with suboptimal cyclophosphamide, achieved complete remissions in most animals and equaled or even exceeded the activity of optimal cyclophosphamide. Collectively, our findings provide the rationale for testing the clinical advantages of adding ITF2357 to current therapies for the still very ominous c‐Myc‐overexpressing lymphomas. They equally provide the proof‐of‐concept for its clinical evaluation in rational combination with the promising inhibitors of B‐cell receptor and PI3K/Akt/mTOR axis currently in the process of development.