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| Status |
Public on Jan 01, 2016 |
| Title |
Gene expression profiling of L-540, SUP-HD1, KM-H2 and L-428 Hodgkin lymphoma cell lines after in vitro and in vivo treatment with the dual PI3K/ERK inhibitor AEZS-136 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Disease relapse and resistance to chemotherapy represent challenging issues in a subset of Hodgkin Lymphoma (HL) patients. Activity and mechanism(s) of action of a novel PI3K/ERK dual inhibitor AEZS-136 (Æterna Zentaris GmbH, Germany, EU) were examined in L-540, SUP-HD1, KM-H2 and L-428 cell lines. Despite exposure to AEZS-136 induced a significant cell growth inhibition (range, 30-80%), levels of caspase-independent cell death and mitochondrial dysfunction, were only observed in L-540 (62 ±9 vs 14 ±3%, P ≤.0001) and SUP-HD1 (46 ±2% vs 15 ±2%, P ≤.0001) cells. Gene expression profiling indicated that the effects of AEZS-136 treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to AEZS-136 resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented AEZS-136-induced ROS production, mitochondrial injury, activation of JNK and cell death. Knockdown experiments identified the immediate early response 3 (IER3) as a key signaling molecule that mediates AEZS-136-resistance to oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 40-70% reduction in tumor burden (P < 0.0001) and a 10-fold increase in tumor necrosis in AEZS-136-treated animals compared to control mice. These data support further clinical evaluation of AEZS-136 in refractory/relapsed HL.
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| Overall design |
The Hodgkin lymphoma cell lines were 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. 4x106 HL cells were seeded in 75 cm2 flask and, after 24 hrs, cells were treated with 10 µM AEZS-136 (Aeterna Zentaris, Frankfurt, Germany, EU) in culture medium for 24 hours. At the end of treatment, cells were collected and RNA extracted.
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| Contributor(s) |
Stirparo GG |
| Citation(s) |
27767172 |
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| Submission date |
Jun 27, 2014 |
| Last update date |
Mar 28, 2020 |
| Contact name |
Giuliano Giuseppe Stirparo |
| E-mail(s) |
[email protected]
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| Organization name |
Cerevance ltd
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| Street address |
418 Cambridge Science Park Milton Rd
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| City |
Cambridge |
| State/province |
Cambridgeshire |
| ZIP/Postal code |
CB4 0PZ |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA253826 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE58899_Non-normalized_data.txt.gz |
4.2 Mb |
(ftp)(http) |
TXT |
| GSE58899_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| Processed data included within Sample table |
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