ENA0000GenomicsMultiomicsIRCSS Istituto Nazionale Tumorihttps://www.ebi.ac.uk/ena/browser/view/PRJNA274135Homo sapiensRelapsed/refractory Hodgkin 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 dramatic 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 ≤.0001) and a 4-fold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared to mice that received the single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL. Overall design: The Hodgkin lymphoma cell line HDLM-2 was obtained from the DSMZ (Braunschweig, Germany, EU). Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 20% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37°C in a water-saturated atmosphere of 5% CO2 in air. 10x10^6 HDLM-2 cells were seeded in 75 cm2 flask and, after 24 hrs, cells were treated with 100 nM Givinostat (Italfarmaco SpA, Milan, Italy, EU) and/or 5 µM sorafenib (Bayer, Berlin,
Germany, EU) in culture medium for 24 hours. At the end of treatment, cells were collected and RNA was extracted.ENABAY 545 9085, Profiling, Transcriptome, BAY 673472, BAY 43 9006, Monitorings, BAY5459085, 2-Pyridinecarboxamide, Gene, Gene Expression Profilings, Gene Expression, Differential Display, Transcript Expression Analysis, transcription profiling, mRNA Differential Displays, BAY-673472, Transcript Expression Analyses, Sorafenib N-Oxide, Gene Expression Pattern Analysis, BAY 43-9006, Gene Expression Monitorings, Sorafenib Tosylate, Analysis, Profilings, mRNA Differential Display, 4-(4-((((4-chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-, gene expression profiling, Gene Expression Monitoring, BAY 439006, Sorafenib N Oxide, Transcriptome Profiling, Analyses, mRNA, Transcriptome Profilings, BAY 5459085, Transcriptomics, Differential Displays, Transcript Expression, Transcriptome Analysis, Transcriptome Analyses, HDLM-2, Monitoring, Gene Expression Analysis, Gene Expression Analyses, BAY-545-9085, BAY 545-9085, Nexavar, Expression Analysis, Expression Analyses, 4-(4-(3-(4-Chloro-3-trifluoromethylphenyl)ureido)phenoxy)pyridine-2-carboxylic acid methyamide-4-methylbenzenesulfonate.human being, human., man0.00.00.00.00.00falseHomo sapiensGene expression profiling of HDLM-2 Hodgkin lymphoma cell line after in vitro and in vivo treatment with Givinostat in combination with Sorafenib2022-05-122015-03-01PRJNA274135GSE65479245615199606