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Lymphoma

BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts

Leukemia volume 28, pages 1861–1871 (2014)Cite this article

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Abstract

Relapsed/refractory Hodgkin’s lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70–80%) and a marked increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P<0.0001), a 5- to 15-fold increase in BIM expression (P⩽0.0001) and a fourfold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared with mice that received single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL.

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Acknowledgements

This work was supported by grants from the Ministry of Health (Ricerca Finalizzata 2010 to CC-S).

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Authors and Affiliations

  1. Department of Oncology and Hematology, Humanitas Cancer Center - Humanitas Clinical and Research Center, Milano, Italy

    S L Locatelli, G G Stirparo, S Tartari, E Saba & C Carlo-Stella

  2. Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy

    S L Locatelli, G G Stirparo & C Carlo-Stella

  3. Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy

    L Cleris & A Anichini

  4. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

    M Pierdominici

  5. Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy

    W Malorni

  6. Istituto San Raffaele Sulmona, Sulmona, Italy

    W Malorni

  7. Pathology Department, CRO Aviano, Aviano, Italy

    A Carbone

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  1. S L Locatelli
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Locatelli, S., Cleris, L., Stirparo, G. et al. BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts. Leukemia 28, 1861–1871 (2014). https://doi.org/10.1038/leu.2014.81

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