Transcriptomics

Dataset Information

5

Gene expression profiling of HDLM-2 Hodgkin lymphoma cell line after in vitro and in vivo treatment with Givinostat in combination with Sorafenib


ABSTRACT: 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 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.

ORGANISM(S): Homo sapiens  

SUBMITTER: Loris De Cecco   L De Cecco  G Stirparo  A Anichini 

PROVIDER: E-GEOD-65479 | ArrayExpress | 2015-03-01

SECONDARY ACCESSION(S): GSE65479PRJNA274135

REPOSITORIES: GEO, ArrayExpress

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Publications

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

Locatelli S L SL   Cleris L L   Stirparo G G GG   Tartari S S   Saba E E   Pierdominici M M   Malorni W W   Carbone A A   Anichini A A   Carlo-Stella C C  

Leukemia 20140224 9


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 profilin  ...[more]

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