(T0930-05-28) Antipsychotic Agent Pimavanserin, a Potential Therapy for Glioblastoma

Purpose: Glioblastoma multiforme (GBM) is a highly aggressive grade IV malignant brain tumor with an average survival time of 12 - 18 months. Although there are several current treatment strategies, they all prove to be inefficient as the 5-year survival rate still remains at 5%. Drug resistance and passage through the blood-brain barrier (BBB) are still the major hurdles of GBM chemotherapy. In the current study, we evaluated the anti-cancer effects of an FDA-approved anti-psychotic drug Pimavanserin tartrate (PVT) for GBM.

Methods: Cytotoxicity assays were performed on SF268, SF188, SF295, U251, and CT2A-Luc GBM cell lines using SRB colorimetric assay. Colony formation capability was analyzed for various GBM cell lines. Apoptosis was confirmed by analyzing the percentage of apoptotic cells by Annexin assay. Apoptotic markers and various oncoproteins' expressions were investigated using the western blot technique. The effect of PVT on the cell cycle was measured using propidium iodide measured in flow cytometry. In vivo study using an orthotopic tumor model in mice is currently in progress.

Results: We observed a significant suppression in the proliferation of different human and murine GBM cell lines viz. SF268, SF188, SF295, U251, and CT2A-Luc with the IC₅₀ in the range of 5µM to 8µM at 48 and 72 hours after treatment. The colony-forming ability of the GBM cells was also significantly inhibited by PVT. Induction of apoptosis by PVT was observed in a dose-dependent manner in the annexin assay; wherein 10µM PVT showed a 70% increase in apoptotic cells as compared to control. An increase in Cleaved caspase-3 expression was also observed. The anti-proliferative and apoptosis-inducing effects of PVT were associated with the inhibition of PI3K, Akt, and MAPK in various GBM cell lines. Furthermore, we observed that PVT causes G1 phase cell-cycle arrest in GBM cells.

Conclusion: Our findings provide a robust platform signifying the potential of PVT to treat GBM, orchestrated via the PI3K/Akt and MAPK signaling.