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E-GEOD-65483 - Gene expression profiling of L-540 Hodgkin lymphoma cell line after in vitro and in vivo treatment with Givinostat in combination with Sorafenib

Status
Released on 1 March 2015, last updated on 7 March 2015
Organism
Homo sapiens
Samples (12)
Array (1)
Protocols (7)
Description
Relapsed/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. The Hodgkin lymphoma cell line L-540 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 L-540 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.
Experiment type
transcription profiling by array 
Contacts
Loris De Cecco <loris.dececco@istitutotumori.mi.it>, A Anichini, G Stirparo, L De Cecco
Citation
BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts. Locatelli SL, Cleris L, Stirparo GG, Tartari S, Saba E, Pierdominici M, Malorni W, Carbone A, Anichini A, Carlo-Stella C. , PMID:24561519
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-65483.idf.txt
Sample and data relationshipE-GEOD-65483.sdrf.txt
Processed data (1)E-GEOD-65483.processed.1.zip
Additional data (1)E-GEOD-65483.additional.1.zip
Array designA-MEXP-1171.adf.txt
Links