Introduction: Protein phosphatase 2A (PP2A) is a potential target for treating inflammation, neurodegeneration, and cancer. Reduced levels of PP2A are associated with neurodegeneration, along with increased levels of endogenous PP2A inhibitors. In cancer treatment, PP2A is a tumor suppressor, the inhibition of which hyperactivates multiple oncogenic signaling pathways and could be lethal to cancer cells particularly in combination with other anticancer drugs.

Methods: The effects of PP2A inhibitor (LB-100) alone and in combination with either Wee1 kinase inhibitor (adavosertib), paclitaxel, or doxorubicin were assessed on primary human glioblastoma grade 4 cells. The methodology included high-throughput imaging with ImageExpress PICO, real-time quantitative cell analysis with xCELLigence, and cell death induction analysis with flow cytometry. We conducted a behavioral study using C57BL/6J mice to assess cognitive deficiencies after treatment with LB-100. The mice received intraperitoneal injections of LB-100 at a dose of 1.5 mg/kg on days 1, 3, and 5, repeated in 5 cycles.

Results: Our initial findings indicate that glioblastoma cells were sensitive to LB-100, while its combinations with adavosertib and doxorubicin were synergistic. Additionally, continuous LB-100 treatment for 3 weeks resulted in significant body weight loss but did not show any noticeable cognitive changes.

Conclusions: It is important to investigate the effects of PP2A inhibition on neurodegeneration to assess its potential as a cancer therapy with minimal impact on cognition.