ArticleScientific reports2016
Dual PI3K/ERK inhibition induces necroptotic cell death of Hodgkin Lymphoma cells through IER3 downregulation.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 21 citations in OpenAlex.
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- The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope.Communications biology · 2022Article
- Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy.Acta pharmaceutica Sinica. B · 2022Review
- KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders.Cancers · 2022Review
- Omega-Class Glutathione Transferases of Carcinogenic Liver Fluke,Antioxidants (Basel, Switzerland) · 2021Article
- 2-D08 treatment regulates C2C12 myoblast proliferation and differentiation via the Erk1/2 and proteasome signaling pathways.Journal of muscle research and cell motility · 2021Article
- Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities.Neural plasticity · 2020Review
- Carbon Monoxide Attenuates Lipopolysaccharides (LPS)-Induced Acute Lung Injury in Neonatal Rats via Downregulation of Cx43 to Reduce Necroptosis.Medical science monitor : international medical journal of experimental and clinical research · 2019Article
- Increased expression of immediate early response gene 3 protein promotes aggressive progression and predicts poor prognosis in human bladder cancer.BMC urology · 2018Article
- Necrostatin-1 protects C2C12 myotubes from CoCl2-induced hypoxia.International journal of molecular medicine · 2018Article
- Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways.NPJ precision oncology · 2018Article
- Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma.Hematology. American Society of Hematology. Education Program · 2017Review
- Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
PI3K/AKT and RAF/MEK/ERK pathways are constitutively activated in Hodgkin lymphoma (HL) patients, thus representing attractive therapeutic targets. Here we report that the PI3K/ERK dual inhibitor AEZS-136 induced significant cell proliferation inhibition in L-540, SUP-HD1, KM-H2 and L-428 HL cell lines, but a significant increase in necroptotic cell death was observed only in two out of four cell lines (L-540 and SUP-HD1). In these cells, AEZS-136-induced necroptosis was associated with mitochondrial dysfunction and reactive oxygen species (ROS) production. JNK was activated by AEZS-136, and AEZS-136-induced necroptosis was blocked by the necroptosis inhibitor necrostatin-1 or the JNK inhibitor SP600125, suggesting that JNK activation is required to trigger necroptosis following dual PI3K/ERK inhibition. Gene expression analysis indicated that the effects of AEZS-136 were associated with the modulation of cell cycle and cell death pathways. In the cell death-resistant cell lines, AEZS-136 induced the expression of immediate early response 3 (IER3) both in vitro and in vivo. Silencing of IER3 restored sensitivity to AEZS-136-induced necroptosis. Furthermore, xenograft studies demonstrated a 70% inhibition of tumor growth and a 10-fold increase in tumor necrosis in AEZS-136-treated animals. Together, these data suggest that dual PI3K/ERK inhibition might be an effective approach for improving therapeutic outcomes in HL.
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