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Published on: August 13, 2017
Pre-Clinical Study Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Neuroblastoma
Laura V Bownes1, Raoud Marayati1, Colin H Quinn1
1Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Background:
Protein phosphatase 2A (PP2A) functions as an inhibitor of cancer cell proliferation, and its tumor suppressor function is attenuated in many cancers. Previous studies utilized FTY720, an immunomodulating compound known to activate PP2A, and demonstrated a decrease in the malignant phenotype in neuroblastoma. We wished to investigate the effects of two novel PP2A activators, ATUX-792 (792) and DBK-1154 (1154).
Methods:
Long-term passage neuroblastoma cell lines and human neuroblastoma patient-derived xenograft (PDX) cells were used. Cells were treated with 792 or 1154, and viability, proliferation, and motility were examined. The effect on tumor growth was investigated using a murine flank tumor model.
Results:
Treatment with 792 or 1154 resulted in PP2A activation, decreased cell survival, proliferation, and motility in neuroblastoma cells. Immunoblotting revealed a decrease in MYCN protein expression with increasing concentrations of 792 and 1154. Treatment with 792 led to tumor necrosis and decreased tumor growth in vivo.
Conclusions:
PP2A activation with 792 or 1154 decreased survival, proliferation, and motility of neuroblastoma in vitro and tumor growth in vivo. Both compounds resulted in decreased expression of the oncogenic protein MYCN. These findings indicate a potential therapeutic role for these novel PP2A activators in neuroblastoma.
Insights
Novel protein phosphatase 2A (PP2A) activators, ATUX-792 and DBK-1154, show promise in treating neuroblastoma by inhibiting cancer cell growth and reducing MYCN expression.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Protein phosphatase 2A (PP2A) is a tumor suppressor whose function is impaired in many cancers.
- Previous research demonstrated that FTY720, a PP2A activator, reduced the malignant phenotype in neuroblastoma.
- This study explores two novel PP2A activators, ATUX-792 (792) and DBK-1154 (1154).
Purpose of the Study:
- To investigate the therapeutic potential of novel PP2A activators, 792 and 1154, in neuroblastoma.
- To determine the effects of 792 and 1154 on neuroblastoma cell viability, proliferation, and motility.
- To assess the impact of these compounds on tumor growth in vivo.
Main Methods:
- Neuroblastoma cell lines and patient-derived xenograft (PDX) cells were treated with 792 or 1154.
- Cellular viability, proliferation, and motility assays were performed.
- In vivo efficacy was evaluated using a murine flank tumor model.
Main Results:
- Both 792 and 1154 activated PP2A, leading to decreased neuroblastoma cell survival, proliferation, and motility.
- Immunoblotting showed reduced MYCN protein expression with increasing concentrations of 792 and 1154.
- Treatment with 792 resulted in significant tumor necrosis and reduced tumor growth in vivo.
Conclusions:
- Novel PP2A activators 792 and 1154 effectively inhibit neuroblastoma growth both in vitro and in vivo.
- These compounds decrease the expression of the oncogenic MYCN protein.
- ATUX-792 and DBK-1154 represent potential novel therapeutics for neuroblastoma treatment.
