Experimental Evaluation of QY-69: A Butyrylcholinesterase Inhibitor with Anti-Glioblastoma Efficacy.

Abstract

Introduction: Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor, characterized by poor prognosis. Moreover, cognitive impairment from the tumor and its treatments compromises patients' quality of life. Butyrylcholinesterase (BChE) inhibition enhances cognitive function. Notably, BCHE is overexpressed in GBM tissues; its downregulation suppresses tumor cell proliferation, migration, and invasion. This study aimed to identify a BChE inhibitor with dual functionality: anti-GBM efficacy and cognitive protection via modulation of neuro-inflammation.

Methods: QY-69 was identified from an in-house BChE inhibitor library through cytotoxicity-based screening. Its anti-GBM effects were evaluated through colony formation, wound healing, and transwell assays. Orthotopic GBM mice were treated with QY-69 orally for 15 days. Tumor progression, cognitive function (Morris water maze), and neuroinflammation (microglia and astrocyte immunofluorescence) were analyzed.

Results: QY-69 exhibited significant antiproliferative activity at micromolar concentrations. In vitro assays demonstrated significant inhibition of GBM cell growth, migration, and invasion. Behavioral impairment in mice was improved, and the activation of astrocytes and microglia in peritumoral tissues was reduced, indicating a decrease in neuroinflammation.

Discussion: QY-69 demonstrated dual therapeutic potential in GBM by inhibiting tumor progression and alleviating cognitive impairment. However, its precise molecular mechanisms remain to be elucidated. Future research should employ transcriptomic and proteomic approaches to elucidate the molecular basis of its anti-GBM activity.

Conclusion: QY-69, a BChE inhibitor, exhibits potent anti-GBM activity and confers cognitive protection, positioning it as a promising dual-action therapeutic candidate. By inhibiting tumor progression and reducing neuro-inflammation, it may enhance both survival and quality of life in GBM patients.