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.
BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts / S.L. Locatelli, L. Cleris, G. Stirparo, S. Tartari, E. Saba, M. Pierdominici, W. Malorni, A. Carbone, A. Anichini, C. Carlo-Stella. - In: LEUKEMIA. - ISSN 0887-6924. - 28:9(2014 Sep), pp. 1861-1871.
|Titolo:||BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts|
LOCATELLI, SILVIA LAURA (Primo)
CARLO STELLA, CARMELO (Ultimo)
|Parole Chiave:||animals; apoptosis; apoptosis regulatory proteins; carbamates; cell line, tumor; histone deacetylase inhibitors; Hodgkin disease; humans; imidazoles; indoles; membrane proteins; mice; mice, scid; necrosis; niacinamide; phenylurea compounds; proto-oncogene proteins; reactive oxygen species; up-regulation; xenograft model antitumor assays|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||set-2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/leu.2014.81|
|Appare nelle tipologie:||01 - Articolo su periodico|