Related Experiment Video
Updated: Mar 29, 2026
Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
Fimepinostat Promotes Apoptosis and Decreases Cytokine Secretion in NF2-Related Human Schwannoma Cells
Anna Nagel1, Ethan W Hass1, Hollie Hayes1
1Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Abstract:
There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression.
Insights
Fimepinostat shows promise for treating neurofibromatosis type 2-related schwannomatosis (NF2-SWN). This dual inhibitor promotes apoptosis in schwannoma cells, offering a potential new therapeutic avenue for this rare condition.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- No approved drug therapies exist for neurofibromatosis type 2-related schwannomatosis (NF2-SWN).
- Current treatments like surgery and radiation are not curative and can worsen neurological deficits.
- Fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, was previously identified as a potential therapeutic agent.
Purpose of the Study:
- To confirm the efficacy of fimepinostat in preclinical schwannoma models.
- To identify the pro-apoptotic signaling pathways targeted by fimepinostat.
- To evaluate fimepinostat's potential as a drug intervention for NF2-SWN.
Main Methods:
- Testing fimepinostat in human schwannoma cell lines and patient-derived cells.
- Utilizing a sciatic nerve allograft model in vivo.
- Elucidating apoptotic pathways via immune assays, flow cytometry, imaging, proteome, and acetylome analysis.
Main Results:
- Fimepinostat induced p21-dependent cell cycle inhibition and caspase-3-dependent apoptosis.
- Upregulation of TRAIL R2 and downregulation of TNFR1, YAP, and apoptosis inhibitors were observed.
- Fimepinostat reduced pro-inflammatory cytokine and chemokine secretion associated with merlin loss.
Conclusions:
- Fimepinostat demonstrates significant preclinical efficacy against schwannomas.
- The drug effectively targets key apoptotic and cell cycle regulatory pathways.
- Fimepinostat represents a promising therapeutic candidate for NF2-SWN, potentially inducing tumor regression.
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:31The Intrinsic Apoptotic Pathway