Abstract
Simple SummaryDespite significant advancements in neuroblastoma therapy, over half of the children with high-risk neuroblastoma will suffer disease relapse. Protein phosphatase 2A (PP2A) is a tumor suppressor that is decreased in neuroblastoma. Previous studies with FTY720, an immunomodulatory agent that activates PP2A, led to a decreased malignant phenotype in neuroblastoma. To activate PP2A without issues associated with the use of an immunomodulator, we investigated two novel PP2A-activating compounds, ATUX-792 and DBK-1154, designed for improved efficacy and fewer side effects. We aimed to demonstrate that ATUX-792 and DBK-1154 would decrease neuroblastoma cell survival and tumor growth with the goal of providing pre-clinical data to support advancing these compounds into the clinical arena.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.
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