Pleiotropic antitumor effects of the pan-HDAC inhibitor ITF2357 against c-Myc-overexpressing human B-cell non-Hodgkin lymphomas

Abstract

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. What's new? c-Myc plays a critical role in aggressive B-cell non-Hodgkin lymphomas and multiple myelomas, and is associated with extremely poor prognosis. It hasn't been easy, though, to directly inhibit c-Myc. In this study, the authors found that a histone-deacetylase inhibitor (HDAC) called ITF2357 down-regulated c-Myc protein expression, and that microRNAs (miRNAs) may be involved. ITF2357 also significantly enhanced chemotherapy against human Burkitt's lymphoma in mice. These results suggest that indirectly interfering with c-Myc's oncogenic functions is a promising therapeutic strategy, and that ITF2357 may be a valuable addition to conventional treatments for c-Myc-overexpressing lymphomas. © 2014 UICC.