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| Status |
Public on Mar 01, 2015 |
| Title |
Gene expression profiling of L-540 Hodgkin lymphoma cell line after in vitro and in vivo treatment with Givinostat in combination with Sorafenib |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
De Cecco L, Anichini A, Stirparo G |
| Citation(s) |
24561519 |
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| Submission date |
Jan 30, 2015 |
| Last update date |
Aug 16, 2018 |
| Contact name |
Loris De Cecco |
| E-mail(s) |
loris.dececco@istitutotumori.mi.it
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| Organization name |
IRCSS Istituto Nazionale Tumori
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| Street address |
via Venezian 1
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| City |
Milan |
| ZIP/Postal code |
20133 |
| Country |
Italy |
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| Platforms (1) |
| GPL6947 |
Illumina HumanHT-12 V3.0 expression beadchip |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE31060 |
Gene expression analysis of Hodgkin lymphoma cell lines treated with the AKT inhibitor perifosine and the multikinase inhibitor sorafenib |
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| Relations |
| BioProject |
PRJNA274139 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE65483_RAW.tar |
6.2 Mb |
(http)(custom) |
TAR |
| GSE65483_non-normalized.txt.gz |
2.7 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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